<p>Regenerative medicine holds significant promise for the treatment of chronic diseases by harnessing the body’s innate capacity to repair and restore physiological function. However, regenerative activity declines markedly with age, a phenomenon traditionally attributed to depletion/exhaustion of progenitor cell pools. We propose an alternative, complementary mechanism: that age-associated accumulation of senescent cells contributes to impaired regeneration through the secretion of “anti-regenerative” factors. Senolytic therapies, which selectively eliminate senescent cells, may therefore exert therapeutic effects in part by de-repressing endogenous regenerative pathways. If senolytics restore progenitor cell function, their use in combination with interventions known to stimulate endogenous progenitor activity, yet not fully optimized for clinical translation, may provide a powerful strategy to enhance tissue repair. In this review, we examine current research on cellular senescence and the therapeutic potential of senolytics across diverse chronic disease contexts. We summarize the presence and role of endogenous regenerative cells in multiple organ systems and highlight mechanisms by which senescent cell-derived secretory factors inhibit regeneration. Finally, we propose potential applications in which senolytic therapy could be leveraged to augment both homeostatic regeneration and regeneration stimulated by therapeutic interventions.</p>