Oncogene-induced senescence (OIS) is a well-documented phenomenon both in vitro and in vivo as a tumor-suppression mechanism. It functions as a barrier to tumor initiation and progression. However, tumor cells develop a sophisticated yet not well-understood mechanism to overcome and subsequently repress cellular senescence to facilitate its progression. Here we report our findings on oncogene-induced senescence and therapy-induced senescence in human melanoma cells. Mutated BRAF or NRAS oncogenes can induce senescence in some but not all melanoma cells, whereas some small molecules are more potent triggers of premature senescence in melanoma cells than others. We established an integrated FACS approach to quantify the heterogeneous response of melanoma cells to therapies. Importantly, we identified two distinct forms of therapy-induced senescence, which were dependent on the type of therapy. By implementing a systems biology approach, we identified core senescence components that were sufficient and necessary for the induction of therapy-induced senescence in melanoma cells. Furthermore, we showed that oncogene-induced senescence in normal cells resembled therapy-induced senescence in cancer cells based on gene expression profiles. Our work unraveled an intimate link between autophagy and senescence in melanoma cells undergoing therapy-induced senescence. We proved that combination therapy might not necessarily lead to synergy but antagonism, depending on which pathways were targeted. Thus we present the rationale for utilizing pro-senescence therapy as a novel therapeutic strategy for patients with advanced melanoma, and suggest that pro-senescence therapy should be combined with other targeted therapies or immunotherapies to maximize cell death.