The alteration in expression of B cell lymphoma-2 (Bcl-2) family of protein members in cancer is involved mainly in the regulation of apoptosis. Bcl-2 family proteins are currently used as major targets in the development of methods to improve treatment outcomes for cancer patients that underwent clinical trials. Although many agents have been developed for targeting Bcl-2 in the past decade, some previous attempts to target Bcl-2 have not resulted in beneficial clinical outcome for reasons unknown. Here, we propose that this was due in part for not considering the cellular level of a different antiapoptotic protein, i.e., galectin-3 (Gal-3). Gal-3 is a member of the β-galactoside binding protein family and a multifunctional oncogenic protein which regulates cell growth, cell adhesion, cell proliferation, angiogenesis, and apoptosis. Gal-3 is the sole protein that contains the NWGR anti-death motif of the Bcl-2 family and inhibits cell apoptosis induced by chemotherapeutic agents through phosphorylation, translocation and regulation of survival signaling pathways. It is now established that Gal-3 is a candidate target protein to suppress antiapoptotic activity and anticancer drug resistance. In this review, we describe the role and relevance of Gal-3 and Bcl-2 protein family in the regulation of apoptosis and propose a novel combination therapy modality. Combination therapy that targets Gal-3 could be essential for improvement of the efficacy of Bcl-2 targeting therapy in cancers and should be studied in future clinical trials. Otherwise, not considering Gal-3 cellular level could lead to trial failure.