Three BTK inhibitors are now approved for previously treated mantle cell lymphoma: ibrutinib, acalabrutinib, and zanubrutinib. Multiple other treatments with a similar mechanism of action are also in development (e.g., orelabrutinib). These drugs primarily impact cytotoxicity through the irreversible inhibition of BTK, and they all do this quite well. Notable differences include the relative specificity for BTK, other Tec-family kinases, and unrelated protein tyrosine kinases (e.g., EGFR), which likely account for variability in safety profile. Other clinically relevant differences include half-life and drug-drug interactions. It is likely that these drugs do not all behave identically in all situations, and some investigators (largely with industry sponsorships) have used preclinical and clinical data sets to suggest the superiority of their choice. Dissimilarities in study design and patient populations enrolled in pivotal trials encumber comparison, although intricate statistical maneuvers might help. We would all prefer to use the best drug every time, but without prospective, randomized, double-blind, placebo-controlled, phase 3 trials, that possibility cannot be guaranteed. The major issue facing lymphoma patients today, however, is not which drug is better, but rather how to make them all work better (i.e., combinations). More trials should address this question.—Peter Martin, MD