Mantle cell lymphoma (MCL) is a distinct subtype of B-cell non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) translocation leading to cyclin D1 overexpression and cell cycle dysregulation. Molecular profiling with gene expression and deep sequencing analyses has identified genomic and epigenomic alterations in pathways regulating the cell cycle, DNA damage response, proliferation, and survival, which contribute to disease progression with important prognostic and therapeutic implications. Clinically, the nonnodal MCL subset is notable for leukemic presentation, indolent behavior, and association with hypermutated IGHV and lack of SOX11 expression, which differentiates it from the conventional nodal MCL. In addition to the Mantle Cell Lymphoma International Prognostic Index score and proliferative gene signatures, 17p/TP53 and 9p/CDKN2A alterations, and genomic complexity have emerged as clinically useful biomarkers of high-risk disease associated with aggressive disease behavior, resistance to chemotherapy, and poor overall survival. Although intensive chemoimmunotherapy regimens that incorporate high-dose cytarabine and stem cell transplantation have improved survival in young and fit MCL patients, the introduction of Bruton tyrosine kinase inhibitors and other novel agents has made effective outpatient-based treatment accessible to nearly all MCL patients. Optimizing combinations of novel agents in the relapsed setting and moving novel agents to the first-line setting have the potential to fundamentally change the MCL therapeutic landscape for the better, especially for patients ineligible for chemotherapy or those with high-risk mutations that are resistant to chemotherapy.