Abstract Background Bladder cancer with divergent differentiation (BCDD) comprises a heterogenous group of tumors with a poor prognosis, and differential expression of nectin‐4 and programmed death ligand‐1 (PD‐L1) has been reported in BCDD. Importantly, nectin‐4 expression in bladder cancer is associated with response to enfortumab vedotin, and PD‐L1 expression is associated with responses to immune checkpoint inhibitors (ICIs). Methods The authors conducted a retrospective review identifying 117 patients with advanced or metastatic BCDD who were treated at Winship Cancer Institute from 2011 to 2021. They performed immunohistochemistry staining for nectin‐4 and PD‐L1 expression by histologic subtype as well as genomic analysis of these patients, including RNA sequencing, whole‐exome sequencing, and fusion detection analysis as well as a subgroup genomic analysis of patients with BCDD who received ICIs. Results The results indicated that nectin‐4 expression was highest in the groups who had the squamous and plasmacytoid subtypes, whereas the group that had the sarcomatoid subtype (70.8%) had the highest proportion of PD‐L1–positive patients. Genomic analysis yielded several key findings, including a 50% RB1 mutation rate in patients who had small cell BCDD, targetable PIK3CA mutations across multiple subtypes of BCDD, and significantly higher expression of TEC in responders to ICIs. Conclusions In this study, the authors identified clinically relevant data on nectin‐4 and PD‐L1 expression in patients with rare bladder tumors. They also identified several novel findings in the genomic analysis that highlight the role of precision medicine in this population of patients. Larger, prospective studies are needed to validate these hypothesis‐generating data. In this study, the authors performed a retrospective analysis focused on the histologic and genomic characterization of bladder cancer with divergent differentiation. The results indicated that nectin‐4 expression was highest in patients with squamous and plasmacytoid differentiation, whereas patients who had sarcomatoid differentiation (70.8%) had the highest proportion of programmed death ligand‐1–positive disease, and several novel findings were identified in the genomic analysis that have potential clinical implications for these patients with rare tumors.