INTRODUCTION: Mantle cell lymphoma (MCL) is an aggressive B cell non-Hodgkin lymphoma (NHL) that is characterized by the translocation t(11;14)(q13;q32) and a poor response to rituximab-anthracycline-based chemotherapy. Intensive regimens offer durable response, but a subgroup of MCL patients will not be eligible for those regimens and hence are candidates for less toxic, novel therapies based on a more tailored personalized approach. AREAS COVERED: This article examines the molecular landscape of MCL, drug resistance mechanisms, and the data on emerging targeted therapies. EXPERT OPINION: DNA damage pathway, ATM mutation, TP53, and epigenetic abnormalities are key drivers of MCL. sBCL2, PARP, ATR, CDK inhibitors or epigenetic modifiers are among the most promising drugs under investigation in clinical trials. The genomic landscape of MCL suggests two types of disease based on the presence of or alterations which should be the framework of future molecular driven strategies. Among novel drugs, those interacting with the DNA damage response pathway offer the most effective rational for their use in MCL.