Multiple myeloma (MM) remains incurable with conventional treatment approaches, and novel biologically based therapies are therefore urgently needed. Targeted therapies are either under development or already undergoing clinical evaluation predicated upon: identifying genetic abnormalities in myeloma cells to enhance chemoradiosensitivity; interrupting growth or triggering apoptotic signaling cascades in tumor cells; treating both the tumor cell and its microenvironment; enhancing allogeneic and autologous antimyeloma immunity; and characterizing new myeloma antigens for serotherapy. These therapies, alone or in combination with conventional treatments, offer great promise to improve the outcome for patients with MM.