Inhibitors of a number of protein–protein interactions (PPIs) have emerged as potential anticancer drug candidates. Now, Nim et al. describe a novel high-throughput method that uses a pooled lentiviral dropout approach to screen a library of human peptide motifs for PPI inhibitors that specifically decreased viability of a pancreatic cancer cell line (RWP1). Target interactions of hits were identified computationally and a subset validated in vitro. Further analysis of the inhibitors in RWP1 cells revealed their mechanisms of action, which included apoptosis and cell-cycle arrest.