Cellular senescence is historically associated with cancer suppression and aging. Recently, the reach of the senescence genetic program has been extended to include the ability of senescent cells to actively participate in tissue remodelling during many physiological processes, including placental biology, embryonic patterning, wound healing, and tissue stress responses caused by cancer therapy. Besides growth arrest, a significant feature of senescent cells is their ability to modify their immediate microenvironment using a senescence-associated (SA) secretome, commonly termed the SA secretory phenotype (SASP). Among others, the SASP contains growth factors, cytokines, and extracellular proteases that modulate the majority of both the beneficial and detrimental microenvironmental phenotypes caused by senescent cells. The SASP is thus becoming an obvious pharmaceutical target to manipulate SA effects. Herein, we review known signalling pathways underlying the SASP, including the DNA damage response (DDR), stress kinases, inflammasome, alarmin, inflammation- and cell survival-related transcription factors, miRNAs, RNA stability, autophagy, chromatin components, and metabolic regulators. We also describe the SASP as a temporally regulated dynamic sub-program of senescence that can be divided into a rapid DDR-associated phase, an early self-amplification phase, and a late “mature” phase, the late phase currently being the most widely studied SASP signature. Finally, we discuss how deciphering the signalling pathways regulating the SASP reveal targets that can be manipulated to harness the SA effects to benefit therapies for cancer and other age-related pathologies.