Mechanisms of resistance to targeted therapies and potential bypass strategies. Known and hypothesized mechanisms of resistance to ibrutinib (A), idelalisib (B), and venetoclax (C) are outlined along with potential mechanisms to overcome resistance. *Unknown mechanisms which may have the potential to respond to other targeted therapies or chemoimmunotherapies, but may also be considered for salvage with reduced-intensity allogeneic stem cell transplantation or CAR T-cell therapies.