Cellular senescence is a stable cell growth arrest. Senescent cells are metabolically active, as exemplified by the secretion of inflammatory cytokines, chemokines, and growth factors, which is termed senescence-associated secretory phenotype (SASP). The SASP exerts a range of functions in both normal health and pathology, which is possibly best characterized in cancers and physical aging. Recent studies demonstrated that chromatin is instrumental in regulating the SASP both through nuclear transcription and via the innate immune cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in the cytoplasm. Here, we will review these regulatory mechanisms, with an emphasis on most recent developments in the field. We will highlight the challenges and opportunities in developing intervention approaches, such as targeting chromatin regulatory mechanisms, to alter the SASP as an emerging approach to combat cancers and achieve healthy aging.