Multiple myeloma is a B-cell neoplasm that is characterized by clonal proliferation of terminally differentiated plasma cells. Approximately 20,000 new cases are diagnosed each year with a prevalence of about 60,000. Characteristic clinical features include bone disease, hypercalcemia, renal disease, anemia and infections. Advancements in our understanding of multiple myeloma have led to a significant impact in the natural history of the disease. Despite these advances the disease remains incurable and most patients invariably relapse and die. Our understanding of the transformation of normal plasma cells into myeloma cells and the interaction between myeloma cells and elements of the bone marrow microenvironment that sustain proliferation and survival has significantly improved. This knowledge has paved the way for the development of novel drugs that target the genetic and molecular changes that underlie myeloma pathophysiology. In this review we discuss several of these novel agents. We focus on the specific pathways targeted by these drugs and the role they may play in development or progression of multiple myeloma. We also discuss the proposed mechanism of action of these drugs and correlate these to clinical trials where they have been investigated.