Together with crystallographic and biophysical studies that define how the D1–acid box module and HSPG–mediated FGF–FGFR assembly normally enforce an autoinhibited, ligand-dependent state [20,34], these data support a model in which Cys-substituting FGFR3 mutations found in both bladder cancer and skeletal dysplasias drive constitutive signaling by stabilizing a covalent homodimer that at least partially bypasses D1–acid box-mediated autoinhibition and the strict requirement for HSPG-bridged dimerization, resulting in sustained trans-phosphorylation of the intracellular kinase domains. Here, FGFR3 is linked to urinary bladder cancer.