Background: Small cell bladder cancer (SCBC), a malignancy indistinguishable from small cell lung cancer (SCLC), is a rare and aggressive subtype of bladder cancer. Response to chemotherapy in SCBC is poor, yet the standard therapy remains cisplatin and etoposide. Novel therapies based on a better understanding of the underlying mechanisms of transformation are needed. The purpose of this study is to identify potential targets and therapeutic options for this disease, using multiplatform tumor profiling. Methods: In total, 19 small cell bladder cancer specimenswere tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (Sanger or next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (CISH or FISH). Results: Loss of RRM1 (22.2%, 4/18), MGMT (83.3%, 15/18), and TS (26.3%, 5/19) by IHC are associated with potential benefit to traditional chemotherapy. High expression of ERCC1, associated with resistance to platinum-based therapy, was 37.5% (3/8). MRP1, a drug pump associated with resistance to various chemotherapies, was present in 100% (5/5) of specimens. PD-L1 (0%, 0/6) was not expressed. EGFR amplification was detected in 25.0% of patients (1/4). NGS aberrations included TP53 (90.0%), cMET (20.0%, 2/10), RB1 (11.1%), FBXW7 (10%, 1/10), PTEN (10%, 1/10). Sanger sequencing also detected KRAS (100%, 1/1) and PIK3CA (33.3%, 1/3) mutations. Conclusions: Multiplatform tumor profiling identified biomarkers which may clarify treatment dilemmas with this rare cancer. MRP1 overexpression and TP53 loss help explain this cancer’s resistance to traditional chemotherapy and its aggressive course. This approach identified potential therapies, some of which are not typically considered, like temozolomide. Immunotherapy may not be as beneficial in SCBC based on absent PD-L1 expression. NGS and Sanger sequencing identified cell surface receptors and downstream molecules that could be candidates for therapeutic strategies.