Mantle cell lymphoma (MCL) is an uncommon subtype of non-Hodgkin lymphoma in which immunochemotherapy, with or without high-dose therapy, and autologous stem cell transplantation remain standard frontline therapies. Despite their clear efficacy, patients inevitably relapse and require subsequent therapy. In this review, we discuss the key therapeutic approaches in the management of relapsed MCL, covering in depth the data supporting the use of covalent Bruton tyrosine kinase (BTK) inhibitors at first or subsequent relapse. We describe the outcomes of patients progressing through BTK inhibitors and discuss the mechanisms of covalent BTKi resistance and treatment options after covalent treatment with BTKi. Options in this setting may depend on treatment availability, patient's and physician's preference, and the patient's age and comorbidity status. We discuss the rapid recent development of anti-CD19 chimeric antigen receptor T-cell therapy, as well as the utility of allogenic stem cell transplantation and novel therapies, such as noncovalent, reversible BTK inhibitors; ROR1 antibody drug conjugates; and bispecific antibodies.