Mantle cell lymphoma (MCL) represents a relatively uncommon, heterogeneous lymphoma associated with limited overall survival. Targeting of the B-cell receptor pathway in relapsed disease with covalent Bruton tyrosine kinase (cBTK) inhibition has been demonstrated to be highly effective with cBTK inhibitor monotherapy, an established standard of care in relapsed MCL. This review summarizes the recent data strongly suggesting a role for the integration of covalent BTK inhibition in the first-line treatment setting, after the recent presentation and publication of multiple phase II and randomized phase II/III clinical trials demonstrating benefit for the addition of cBTK inhibitors first line. The authors discuss herein the strength and quality of the evidence for therapeutic strategies integrating cBTK inhibitors first line and proposal treatment algorithms on the basis of assumed future availability of this highly active small molecules first line in the near future.