Injection drug use once accounted for half of the new HIV cases each year in Philadelphia. Today, it accounts for less than 6%. This achievement is the result, in large part, of increased access to sterile syringes through needle exchange at Prevention Point Philadelphia. But while tremendous strides have been made in reducing the HIV risk for people who inject drugs (PWID), the story with respect to skin and soft tissue infection (SSTI) and overdose is grim. SSTIs are life-threatening, painful, and remain common among PWID. Rates of fatal overdose, meanwhile, have skyrocketed in recent years, resulting in 907 deaths in 2016 and over 1200 in 2017. Trends for injection-related HIV and injection-related infection and overdose have taken different trajectories because access to sterile injection materials only addresses a portion of the risk environment for injection drug use. Avoiding SSTIs is hard, even with a sterile syringe, when injecting in poorly lit, cold, dirty or otherwise unhygienic spaces. Reversing an overdose is possible with naloxone, but there has to be someone to administer it, and PWID often inject in secluded spaces. Some evidence also suggests that overdose is more likely when PWID inject hurriedly – from fear of assault or arrest – and without the opportunity to taste and control dosing.