Beat all the areas, although the final boss isn't in the game yet.
I play with the timer mutation (you have 4 minutes to beat each level or you insta-die). This is normally more than enough time. But the last area of the game is so freaken hard. Its swarming with supercops and uppercrusters, there are cop bots that are basically walking cameras and most difficult of all, there's barriers that come out of the ground whenever the police are fighting you. Oh and most buildings have invincible walls and/or a bouncer that takes away all your weapons when you enter.
I've only reached this area a couple times and I don't know all the strats yet. Rather than using some kind of elegant strategy, I had purple syringes identified as "invincibility" and the "longer status effects" perk. I cloned a couple purple syringes and whenever I got in a big fight I waded through the hail of machine gun bullets swinging an axe wildly. The situation usually resolved itself from there.
Streets of Rogue, as the slum dweller. I went with a drug+melee based build, and then my level ups never gave me any melee stats (I ended at 1 melee). On the other hand I got a ridiculous set of gear including a rocket launcher and a silencer, which of course I combined.