Background: Malignant pheochromocytomas (MP) are a rare form of endocrine malignancy which can occur in familial and sporadic clinical settings. We performed comprehensive genomic profiling (CGP) to characterize the genomic alterations (GA) in MP and to enable the search for potential therapy targets. Methods: From a series of 181,782 consecutive clinical cases, 43 cases of clinically advanced MP underwent CGP using a hybrid-capture based commercial assay to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and reported as mutations/Mb and microsatellite instability (MSI) was determined on 114 loci. IHC for PD-L1 expression was performed on a subset of patients (DAKO 22C3 antibody). Results: All patients had clinically advanced recurrent and/or metastatic disease. There were 33 (77%) of MP known to have originated in the adrenal gland and 10 (23%) of the MP were sequenced from metastatic site. The primary tumor was used for sequencing in 13 (30%) of the MP cases and a non-primary tumor metastatic site (liver, lung, bone, soft tissue, lymph node, kidney, peritoneal cavity, and chest wall) in 30 (70%) of the MP cases. There were 2.3 GA/tumor. The most frequent un-targetable GA were ATRX (26%), TP53 (21%), SDHB (11%), CTNNB1 (7%), VHL (7%), and CDKN2A/2B, PIK3R2, NOTCH2 and MEN1 (all 5%). The most frequent potentially targetable GA included RET (9%), NF1 (9%) and FGFR1 (5%). PBRM1 GA were found in 2% of MAP. Germline mutations in known cancer predisposition genes were predicted in 7 (16%) of cases involving SDHB (4 cases) and BRCA1, MEN1, and MSH2 (1 case each). The mean TMB was 2.95 mutations/Mb, the median TMB was 2.4 mutations/Mb. 0 (0%) of 33 MP evaluated for MSI had a MSI-High status. Conclusions: MP represent a rare form of endocrine cancer that feature a variety of genomic alterations. Although the GA/tumor is relatively low for MP, CGP can reveal important potential targets for therapy in the metastatic setting including RET, NF1 and FGFR1. MAP do not reveal strong potential for immunotherapy with low TMB, absence of MSI-High status and low (2%) PBRM1 mutation frequencies. Based on this data, further study of CGP as a method of developing precision therapies for MP appears warranted.