Background: FGFR2 and FGFR3 (FGFR2/3) gene alterations are oncogenic drivers found across various cancer types and have been successful targets of drug development. Several FGFR inhibitors (FGFRi) are approved for clinical use, and most are ATP-competitive, reversible inhibitors (1^st-gen). Efficacy of the 1^st-gen FGFRi can be limited by acquired resistance mutations in the FGFR kinase domain, typically molecular brake or gatekeeper mutations, which disrupt compounds binding through conformational changes or through direct steric hindrance, respectively. Irreversible (covalent) FGFRi, such as futibatinib, are in development to overcome kinase domain resistance mutations. However, preclinical evidence indicates that some of the known resistance mutations (eg. V564L) remain insensitive to futibatinib. Methods: To assess the landscape of FGFR-driven cancers and to better understand the prevalence of molecular brake and gatekeeper mutations, we analyzed the distribution of FGFR2/3 alterations in a large clinical genomic research database. This ctDNA-based genomic database was selected for the analysis given that liquid biopsy is a fit-for-purpose method to detect acquired resistance mutations. Results: We identified over 2,100 patients with FGFR2/3 alterations. Non-small cell lung cancer (NSCLC), breast, bladder, and cholangiocarcinoma (CCA) had the highest number of patients with FGFR2/3 alterations. 36% of all FGFR2 alterations across all cancer indications consisted of molecular brake or gatekeeper mutations. This finding was most enriched in CCA and breast cancer where 51% and 57%, respectively, of FGFR2 alterations were molecular brake or gatekeeper mutations. In breast cancer patients, molecular brake mutations were common and represent activating mutations in FGFRi-naïve patients. A small number of FGFR3 gene fusions were detected in CCA patients who had significantly shorter time on 1^st-line treatment and trended toward shorter overall survival when compared to patients with FGFR2 fusions. We also identified CCA patients with FGFR2 fusions and one or more concurrent FGFR2 SNVs; primarily those in the kinase domain and associated with FGFRi resistance. Most of these putative cases of acquired resistance were polyclonal, with 2 or more (up to 8) FGFR2 SNVs coexisting with the fusion. Bladder cancer and NSCLC had the highest numbers of FGFR3 alterations. FGFR2/3 alterations were typically found without other driver mutations in CCA, bladder, and NSCLC patients. However, in breast there was a large overlap between FGFR2/3 alterations and other drivers. Conclusions: Herein, we identify a cohort of patients with FGFR2/3 molecular brake and gatekeeper mutations that may benefit from next-generation FGFR2/3-targeted therapies designed to inhibit a broad spectrum of both primary and secondary resistance mutations.