Mantle cell lymphoma (MCL) is a distinct subtype of non-Hodgkin lymphoma that has been associated with a poor prognosis. Despite improvements in frontline management strategies, including the incorporation of cytarabine, intensification of chemotherapeutic regimens, and consolidation with transplant, MCL remains incurable. Our current understanding of MCL biology affords the opportunity to investigate novel, molecularly targeted therapeutic approaches. This review will focus on innovative drug development for the treatment of relapsed or refractory MCL, including therapies aimed at disrupting the B-cell receptor signaling pathway, regulators of apoptosis, and immunomodulators.