Suit Up - Before setting out on a mission, it's always a good idea to stop by a weapon store, or to give Little Jacob a call, in order to acquire ammunition and fresh body armor. Whether or not you have body armor could mean the difference between failing and completing a mission.
Help From Friends - As you progress through the storyline, Niko will meet new people and make friends in Liberty City. Your friends will like you more if you hang out with them and answer the phone when the call; they will come to resent you if you continuously turn down their invitations or neglect them. Each friend has a special call-in ability which can be utilized once they like you enough. To unlock these abilities, hang out with these characters until their “Like” and “Respect” values are high enough. If their like and respect falls below the required percentage to unlock their special ability, it will be lost until you reach that percentage again. Perhaps the most useful of these special abilities is Little Jacob's (whom you meet early on in the storyline) gun car, which will allow you to purchase weapons at a reduced price. Check out the “Friends” sub-section for a full rundown of all friends and their special abilities.
Take Cover - Cover is of the essence during most firefights; you won't last long if you stand out in the open with guns blazing. Many objects can be used as cover, but you have to choose a suitable piece of cover carefully; enemies above you or behind a nearby piece of cover, may still be able to get a bead on you even while you're behind cover. If you're facing a large number of enemies, keep behind one piece of cover until you have killed as many of them as you can from there before moving up.
Free Aim - While auto-aim returns in this installation of the Grand Theft Auto series, it may be beneficial to turn it off (via the pause “Controls” menu) this time around. Free aiming will allow you to use the cover system much more effectively, and you won't be completely lost in multiplayer if the host decides to disable auto aiming for the match. If you don't want to disable auto-aim completely, you can still free aim with it enabled by half-holding the fire button. It's a good idea to wean yourself off of auto-aim early, especially if you plan to play a lot of multiplayer.
Gray Matter - As is the case with most any gun-heavy action game, delivering a shot to your target's head will deal severe to lethal damage. As such, take advantage of enemies whose heads are visible even while behind cover.
Auto-save - Be sure to make use of the auto-save feature, which can be enabled or disabled via the Game pause menu. Don't rely entirely on the auto-save file, however; it is good practice to save an actual save file every once in awhile, or at the very least before you are finished playing. Healthcare costs are noticeably steep, so you may find yourself using the auto-save feature quite often. The game auto-saves after a mission or after an activity with a friend; make sure you see the saving dialog in the upper-right corner of the screen to ensure that you won't lose progress by reverting to the auto-save file.
The G.P.S. - Now mission objectives are easier to get to than ever; a highlighted route appears on the radar whenever a mission marker is present, directing you through the streets of Liberty City. Keep in mind that the highlighted path is only the shortest, legal route to the location; you can almost always make it to the point in less time by cutting through alleys or driving on the wrong side of the road. The highlighted routes are best used when traveling from one island to another, otherwise it would probably be best to simply ignore it.
Waypoints - You can place a waypoint on any location via the pause Map menu. This waypoint will appear on your radar, along with a green highlighted route.
Time Flies - If you need to pass the time for an event to trigger, you can rest at one of your safe houses to put the clock ahead six hours. There's no need to save your game when you do this; you can just enter the save menu and then exit out for the same effect either way.
Flee The Scene - Shaking the cops works quite differently this time around. To lower your wanted level, you must get out of the flashing circle on your radar and remain out of it until the stars disappear. The circle represents the area of the city that the authorities are actively searching. The zone readjusts each time you are spotted by a police officer, making it more difficult for you to escape. The zone becomes larger with a greater wanted level, so it is best to avoid causing anymore trouble once you are being sought after. Each patrol car and individual officer is marked on your radar, so avoid going down roads that will force an encounter with one.
Fast Travel - Taxis are a quick way of traveling to almost any point in the city. There are plenty of taxis cruising around Liberty City; when you spot one, hail the taxi while on foot and if it pulls over, hold the Enter Vehicle button to enter as a passenger. Taxis will not stop if it is already transporting someone; you can oust the passenger by holding the Enter Vehicle button, but the driver won't stop for you when hailed. Taxis are relatively cheap, and you can even skip the trip entirely—making this the fastest way of moving around the city—for an extra cost. A taxi can take you to or close to any stationary marker on your radar, including waypoints.
Health Matters - There are various ways of replenishing your health if you're close to death. You can take a nap at your safe house; stop by a Cluckin' Bell, Burger Shot, 69th Street Diner or hotdog stand and buy some food; buy a can of soda from a vending machine or vendor, eat out with a friend, pick up a health pack, or even through a private dance at a strip club. If you have money to burn, you could also phone the paramedics and have them rush to your location to heal you; dial 911, select the second extension, and stand on the sidewalk (out of a vehicle) until the ambulance arrives. One of the paramedics will then approach and replenish your health for a price; just train your weapon on him if you change your mind.
Police Cruiser - For easy access to a cop car, first dial 911, select the first extension, wait for the passenger to step out of the police car when it arrives, then enter from the passenger's side to oust the driver.
Birds of a Feather - While driving down the road in a really snazzy car, you may soon find yourself surrounded by several of the same vehicle. This has been a common occurrence in the past few installments of the Grand Theft Auto series; that is, vehicles that spawn on the road tend to be of the same class as the vehicle you are currently driving. You can use this to your advantage if your current car is a wreck; simply pull over and take one of the others on the road. Furthermore, if you're trying to obtain a rare car such as the Infernus, try driving around in a different high-class vehicle and you might just find one.