CONTEXT: Carcinoma in situ (CIS) of the bladder is defined as a high-grade flat lesion confined to the mucosa. Intravesical treatment with bacillus Calmette-Guérin (BCG) is commonly used to reduce the risk of recurrence and progression; however, CIS of the bladder exhibits a heterogeneous clinical behavior and a significant proportion of patients do not show a primary response. OBJECTIVE: To evaluate the available evidence concerning diagnosis, treatment strategies, follow-up, prognosis, and oncological outcomes in patients with CIS of the bladder. EVIDENCE ACQUISITION: A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The search was conducted using the databases PubMed/MEDLINE and Embase. We included randomized controlled trials, systematic reviews, meta-analyses, and observational studies. Outcomes of interest were: (1) diagnostic strategies, (2) first- and second-line treatments, (3) follow-up strategies, and (4) prognosis and oncological outcomes. EVIDENCE SYNTHESIS: Overall 62 articles met the inclusion criteria. Most articles concerned retrospective studies and presented mixed data with other non-muscle-invasive bladder cancer categories. The evidence shows that new optical imaging modalities significantly increase the detection rate of CIS. BCG immunotherapy remains the first-line therapy in patients with CIS of the bladder; however, after treatment, adequate follow-up is necessary. Clinicopathological factors remain the main indicators of response to BCG, recurrence, and progression. CONCLUSIONS: New optical imaging modalities are superior to white light cystoscopy in the detection of CIS of the bladder. There are no robust data that justify consideration of other agents as an alternative to BCG immunotherapy. Despite efforts to identify relevant biomarkers, clinicopathological factors remain the most important prognostic factors. PATIENT SUMMARY: New optical techniques have improved the detection of carcinoma in situ (CIS) of the bladder. Bladder preservation using bacillus Calmette-Guérin immunotherapy remains the cornerstone of the treatment of CIS of the bladder.