Although the advent of biologic therapies has resulted in improved outcomes for patients with multiple myeloma (MM), patients ultimately develop progressively resistant disease. As such, novel approaches are needed. There has been a renewed focus on the development of therapies that would allow redirection of patients' own immune systems to target malignant myeloma cells. Compared with healthy individuals, patients with MM exhibit immune dysregulation and an impaired capacity to develop antitumor immunity. Tumor cells induce tolerance by exploiting native immune pathways responsible for preventing autoimmunity and maintaining immunologic equilibrium. In this review, we will discuss the development of potent humoral and cellular agents directed against myeloma antigens, including novel monoclonal antibodies, myeloma vaccines, and T-cell therapies. We will also discuss the development of immune checkpoint inhibitors and immunomodulatory agents that allow manipulation of the immunologic milieu and support a more robust native immune response. There is a growing interest in combining these 2 approaches-such as pairing antimyeloma vaccines with immune checkpoint blockade-to achieve maximum efficacy of immunotherapy.