This review discusses the role of Bacillus Calmette–Guerin (BCG) and alternative therapies for non-muscle-invasive bladder cancer (NMIBC). BCG is the first-line treatment for NMIBC, inducing an immune response to prevent tumor recurrence and progression. However, some patients do not respond to BCG, leading to the need for alternative therapies. Recent challenges, such as a global BCG shortage, have increased interest in alternatives like mitomycin C, sequential gemcitabine with docetaxel, and systemic pembrolizumab. The review covers the historical and current use of BCG, alternative therapies, and novel treatments approved or under investigation for BCG-unresponsive NMIBC. It highlights the importance of identifying effective alternatives to preserve bladders and reduce the need for radical surgery. Alternative therapies include BCG combination with interferon alpha, intravesical gemcitabine, sequential gemcitabine/docetaxel, mitomycin C, and novel immunotherapies like pembrolizumab and Nadofaragene-Firadenovac. While BCG remains the standard, alternatives are being explored to improve outcomes and reduce side effects. The review emphasizes the need for further research to determine the most effective and safe treatments for NMIBC.This review discusses the role of Bacillus Calmette–Guerin (BCG) and alternative therapies for non-muscle-invasive bladder cancer (NMIBC). BCG is the first-line treatment for NMIBC, inducing an immune response to prevent tumor recurrence and progression. However, some patients do not respond to BCG, leading to the need for alternative therapies. Recent challenges, such as a global BCG shortage, have increased interest in alternatives like mitomycin C, sequential gemcitabine with docetaxel, and systemic pembrolizumab. The review covers the historical and current use of BCG, alternative therapies, and novel treatments approved or under investigation for BCG-unresponsive NMIBC. It highlights the importance of identifying effective alternatives to preserve bladders and reduce the need for radical surgery. Alternative therapies include BCG combination with interferon alpha, intravesical gemcitabine, sequential gemcitabine/docetaxel, mitomycin C, and novel immunotherapies like pembrolizumab and Nadofaragene-Firadenovac. While BCG remains the standard, alternatives are being explored to improve outcomes and reduce side effects. The review emphasizes the need for further research to determine the most effective and safe treatments for NMIBC.