Significant progress in determining the molecular origins and resistance mechanisms of mantle cell lymphoma (MCL) has improved our understanding of the disease's clinical diversity. These factors greatly impact the prognosis of patients with MCL. Given the dynamic alterations in MCL clones and disease evolution, it is crucial to recognize high-risk prognostic factors at diagnosis and relapse. Clinical factors include a high MCL International Prognostic Index score with a high Ki-67 proliferation index, early disease progression within 24 months of first-line treatment, >3 previous lines of therapy at relapse, and an aggressive (blastoid or pleomorphic) histology. Molecular aberrations include dysregulated cyclin D1, an aberrant SOX11-CD70 axis, upregulated Musashi-2, MYC rearrangement, metabolic reprogramming, and epigenetic changes. Other factors that contribute to high-risk MCL include an immune-depleted microenvironment and clone adaptability with complex chromosomal anomalies and somatic mutations in TP53, NSD2, CCND1, CDKN2A, BIRC3, SP140, KMT2D, NFkBIE, SMARCA4, and NOTCH2. Ultra-high-risk MCL is indicated by the coexistence of multiple high-risk prognostic factors in the relapse setting and can portend very short progression-free survival. As MCL treatments advance toward cellular therapies, resistance to anti-CD19 chimeric antigen receptor T-cell therapy is also observed. These findings necessitate revisiting the prognostic impact of high-risk factors, current management strategies, new bi- and trispecific T-cell engagers, combination therapies, novel therapeutic targets, and next-generation clinical trials for patients with high-risk MCL. This article provides a comprehensive update on recognizing and managing high-risk MCL and encompass current practices and future directions.