In this issue of Blood, Martin et al report poor outcomes for ibrutinib-refractory patients with mantle cell lymphoma (MCL). MCL, an uncommon B-cell lymphoma driven by dysregulated cyclin D1, responds well to initial therapy but is destined to relapse. Subsequent single-agent treatments had modest response rates and duration until the advent of ibrutinib. These data are important, given that ibrutinib is not curative, so clinicians will increasingly encounter patients with MCL who require therapy after ibrutinib.