ABSTRACT Adult stem cell therapies are advancing, yet inconsistent clinical benefit indicates that in vitro potency only partially predicts in vivo performance. Framing efficacy through a systems lens, this review integrates three interlocking levers: (i) cell‐intrinsic programs (tissue imprint, transcriptional/epigenetic state, senescence and metabolic fitness), (ii) microenvironmental constraints and designable cues, and (iii) pre‐ and post‐delivery engineering interventions. We highlight how