Bladder cancer accounts for approximately 13,000 deaths annually, and >60,000 new cases will appear this year, making it the fourth and tenth most common cancer among men and women, respectively. The majority of the newly diagnosed cases will be diagnosed prior to muscle invasion, and are thus potentially completely curable. Unfortunately, >20% of patients initially diagnosed with non-muscle invasive bladder cancer will eventually die of their disease despite local endoscopic surgery. Mycobacterium bovis bacillus Calmette-Guérin (BCG) has been used for the treatment of bladder cancer since 1976, and continues to be at the forefront of therapeutic options for this malignancy. Despite its success and worldwide acceptance, the antitumor effector mechanisms remain elusive. BCG therapy induces a massive local immune response characterized by the expression of multiple cytokines in the urine and bladder tissue, and the influx of granulocytes and mononuclear cells into the bladder wall. Findings from our laboratory have demonstrated that tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is induced by BCG treatment, and TRAIL was expressed on polymorphonuclear neutrophils (PMN) in the urine obtained from patients after intravesical BCG instillation. Subsequently, we have determined that BCG and components of the mycobacterial cell wall can directly stimulate the release of soluble TRAIL from PMN through toll-like receptor-2 (TLR2) recognition that is augmented by interferon (IFN). Based on our work and that of others implicating the need for T helper type 1 (Th-1) cytokine responses to BCG therapy for therapeutic results, we propose that TRAIL is released by PMN migrating to the bladder in response to BCG treatment. In addition, IFN acts to augment and prolong the amount of TRAIL released by PMN, resulting in an effective therapeutic outcome.