Summary: Facchinetti and colleagues provide key insights into the evolution of resistance to fibroblast growth factor receptor (FGFR) inhibitors, including the development of kinase domain mutations and activation of the PI3K–AKT signaling axis. In a separate study, Subbiah and colleagues report extensive preclinical data and initial clinical data for RLY-4008, an FGFR2-selective inhibitor that is poised to minimize toxicity and overcome resistance through greater potency and selectivity. See related article by Facchinetti et al., p. 1998 (5). See related article by Subbiah et al., p. 2012 (7).