Background: Genomic studies of cholangiocarcinoma (CCA) have identified actionable alterations in multiple genes including IDH1, IDH2, FGFR2 and BRAF, but no targeted therapies have been approved for this indication. Pemigatinib (formerly INCB054828) is a selective FGFR1-3 inhibitor currently being evaluated in multiple tumor types, including advanced CCA harboring FGFR2 rearrangements. Comprehensive genomic profiling (CGP) was used to identify and enroll advanced CCA patients with FGFR2 rearrangements into FIGHT-202 (NCT02924376). Here we provide an overview of the genomic landscape of advanced CCA and identify actionable alterations. Methods: CGP was performed on tumor samples from 1104 patients with advanced CCA using FoundationOne, a broad-based genomic panel which identifies mutations, rearrangements, and amplifications in 315 cancer genes. Results: The most frequently altered genes in advanced CCA were TP53 (38.1%), CDKN2A/B (28.8%), KRAS (21.9%), ARID1A (15.7%), SMAD4 (11.3%), BAP1 (10.6%), IDH1 (10.5%), PBRM1 (10.0%), FGFR2 (9.4%), ERBB2 (7.6%), PIK3CA (7.0%), MDM2/FRS2 (5.8%), and BRAF (4.7%). FGFR2:BAP1 was the most significantly co-occurring alteration pair (odds ratio = 8.5; q-value = 1.08 x 10^-13, Fisher’s exact test). 42.9% of patients had at least one alteration for which a targeted agent has been either approved or is under investigation. 91 (8.2%) patients had FGFR2 rearrangements, involving 44 unique partner genes, 37 (84.1%) of which were observed only once. The most prevalent FGFR2 rearrangement partner, BICC1, occurred in only 28 (30.7%) FGFR2 rearrangement positive patients. FGFR2 activating point mutations were found in 13 (1.2%) patients. Of 1,091 evaluable patients for microsatellite instability (MSI) or tumor mutational burden (TMB), only 10 (0.9%) were MSI-H and 13 (1.2%) had high TMB (≥ 20 mutations/megabase). None of the MSI-H or TMB-High patients had FGFR2, IDH1 or IDH2 activating alterations. Conclusions: The high frequency (42.9%) of patients with actionable alterations and myriad FGFR2 rearrangement partners strongly support the use of fusion partner-agnostic CGP in advanced CCA.