Polymerization-induced self-assembly (PISA) with (in situ) encapsulation of (therapeutic) cargo has proven to be an efficient preparation method for loaded polymeric micelles and polymersomes, thereby presenting significant opportunities in the field of drug delivery. However, despite extensive research efforts, no significant advances toward systematic in vivo studies or clinical applications have been achieved to date. In this Review, we outline the current state-of-the-art of cargo encapsulation via PISA with a specific focus on developments achieved in the past 5 years. Considering the general requirements for functional drug delivery systems, we identify the major hurdles that still need to be overcome in order to push PISA-derived systems from a promising academic exercise to viable candidates for clinical translation