Approximately 70% to 80% of patients with urothelial carcinomas of the bladder are initially diagnosed with non-muscle invasive disease. Superficial, non-muscle invasive bladder cancers (NMIBCs) are managed with cystoscopic transurethral resection of all visible lesions followed by intravesical chemotherapy and/or immunotherapy. Despite this treatment, up to 70% of these tumors will recur within five years and 15% will ultimately progress to muscle-invasive disease, suggesting that novel therapeutic strategies are necessary. Recent studies have greatly advanced our understanding of urothelial carcinogenesis and have highlighted the distinct molecular pathogenesis of NMIBCs versus muscle-invasive bladder tumors. It is now clear that diverse genetic and epigenetic events are driving the oncogenesis of NMIBCs, thereby attesting to their potential as therapeutic targets for these tumors. This article reviews the molecular pathogenesis of NMIBCs, discusses recently completed and ongoing clinical trials and anticipates the future direction of molecular targeted agents in this disease.