The BCL-2 family of proteins (including the prosurvival proteins BCL-2, BCL-X<sub>L</sub>, and MCL-1) is an important target for the development of novel anticancer therapeutics. Despite the challenges of targeting protein-protein interaction (PPI) interfaces with small molecules, a number of inhibitors (called BH3 mimetics) have entered the clinic and the BCL-2 inhibitor, ABT-199/venetoclax, is already proving transformative. For BCL-X<sub>L</sub>, new validated chemical series are desirable. Here, we outline the crystallography-guided development of a structurally distinct series of BCL-X<sub>L</sub>/BCL-2 inhibitors based on a benzoylurea scaffold, originally proposed as α-helix mimetics. We describe structure-guided exploration of a cryptic "p5" pocket identified in BCL-X<sub>L</sub>. This work yields novel inhibitors with submicromolar binding, with marked selectivity toward BCL-X<sub>L</sub>. Extension into the hydrophobic p2 pocket yielded the most potent inhibitor in the series, binding strongly to BCL-X<sub>L</sub> and BCL-2 (nanomolar-range half-maximal inhibitory concentration (IC<sub>50</sub>)) and displaying mechanism-based killing in cells engineered to depend on BCL-X<sub>L</sub> for survival.