Culture systems for pluripotent stem cell (PSC) expansion enable generation of a nearly unlimited pool of cells for downstream differentiation, disease modeling, drug discovery, and therapeutic applications. While a number of PSC feeder-free medium systems exist, there are many challenges encountered by stem cell scientists across the PSC workflow in today’s applications. Here we sought to improve the robustness and versatility of traditional PSC culture medium systems identify and optimize critical medium components. Through assessment of over 65 different formulations, an optimum medium composition was identified which provides compatibility across the PSC workflow from somatic cell reprogramming, PSC expansion, downstream differentiation, as well as providing support in stressful applications such as gene editing. This system additionally provides versatility, allowing for every-other-day or weekend-free feed schedules and compatibility with a broad range of passaging reagents and matrices. Together this system provides a robust next-generation stem cell medium system for today’s challenging PSC workflow needs. For Research Use Only