It is nearly 40 years since Bacillus Calmette-Guérin (BCG) was first used as an 
immunotherapy to treat superficial bladder cancer. Despite its limitations, to 
date it has not been surpassed by any other treatment. As a better understanding 
of its mechanism of action and the clinical response to it have evolved, some of 
the questions around optimal dosing and treatment protocols have been answered. 
However, its potential for toxicity and failure to produce the desired clinical 
effect in a significant cohort of patients presents an ongoing challenge to 
clinicians and researchers alike. This review summarizes the evidence behind the 
established mechanism of action of BCG in bladder cancer, highlighting the 
extensive array of immune molecules that have been implicated in its action. The 
clinical aspects of BCG are discussed, including its role in reducing recurrence 
and progression, the optimal treatment regime, toxicity and, in light of new 
evidence, whether or not there is a superior BCG strain. The problems of 
toxicity and non-responders to BCG have led to development of new techniques 
aimed at addressing these pitfalls. The progress made in the laboratory has led 
to the identification of novel targets for the development of new 
immunotherapies. This includes the potential augmentation of BCG with various 
immune factors through to techniques avoiding the use of BCG altogether; for 
example, using interferon-activated mononuclear cells, BCG cell wall, or BCG 
cell wall skeleton. The potential role of gene, virus, or photodynamic therapy 
as an alternative to BCG is also reviewed. Recent interest in the immune check 
point system has led to the development of monoclonal antibodies against 
proteins involved in this pathway. Early findings suggest benefit in metastatic 
disease, although the role in superficial bladder cancer remains unclear.