If you're playing the game for the first time, it's like an RPG with no limitations compare to the last Saint games. So for example, in the beginning, you have a limit on what you can upgrade compare to level 50 in which you unlock everything that will help in many ways. So if you're pummeled by bullets, upgrade bullet damage resistance and health boost to allow you to slowly get immune to damage, lowering your chance of dying. Need powerful allies, boost their health and allow up to three in your team.
The list below should help with your decision making skills. The best advice is to build enough money income every time to help you as your reputation goes up. After all, you don't want your weapons to run out or allow your notoriety and police level to go down more quickly. The best benefit by the end of the game is you'll almost be invincible and won't need to waste anymore money on ammo but be able to use it on upgrading weapons.