Failure of myeloma cells to undergo apoptosis plays an important role in the accumulation of myeloma cells within the bone marrow (BM). Moreover, inhibition of drug-induced apoptosis has been indicated as a major contributor of drug resistance in myeloma. The BM microenvironment promotes survival and blocks the apoptotic effects of various cytotoxic agents through the production of cytokines as well as through direct physical interactions. Several antiapoptotic proteins and antiapoptotic signaling cascades have been identified that contribute to the antiapoptotic phenotype of the myeloma cell. In this review, we discuss mechanisms that result in enhanced survival and drug resistance of myeloma cells. Insight into these mechanisms is essential to make progress in the therapy of myeloma.