Bladder cancer is an increasingly important international public health problem, with over 330,000 new cases being diagnosed each year worldwide. In a systematic review and evidence synthesis, the authors investigated the joint effects of the N-acetyltransferase genes NAT1 and NAT2 and cigarette smoking on bladder carcinogenesis. Studies were identified through an exhaustive search of multiple electronic databases and reference lists and through direct contact with study authors and experts. Random-effects meta-analysis was used within a Bayesian framework to investigate individual effects of NAT1 and NAT2 acetylation status on bladder cancer risk, while a novel approach was used to investigate joint effects of these two genes with cigarette smoking. An increased risk of bladder cancer was found in NAT2 slow acetylators (odds ratio = 1.46, 95% credible interval (CI): 1.26, 1.68) but not in NAT1 fast acetylators (odds ratio = 1.01, 95% CI: 0.86, 1.22). The joint effects in the highest risk category (NAT2 slow acetylator, NAT1 fast acetylator, and current or ever cigarette smoking) as compared with the reference category (NAT2 fast acetylator, NAT1 slow acetylator, and never smoking) were associated with an odds ratio of 2.73 (95% CI: 1.70, 4.31). The importance of considering joint effects between genetic and environmental factors in the etiology of common complex diseases is underlined.