2014 marks the 40th anniversary of the seminal discovery by Johannes Rook, in 1974, that trihalomethanes (THMs) were formed by the chlorination of natural organic matter (NOM) in drinking water. Since this discovery, which revolutionized how we viewed drinking water safety and quality, hundreds of other classes of disinfection by-products (DBPs) have been discovered. The finding in 1976 by the US National Cancer Institute that chloroform, the dominant THM, was a rodent carcinogen spurred a large number of epidemiology and toxicology studies into chlorinated drinking water. In 1985, this cancer finding was shown to be wrong. We should now be asking: What do we know about the human health impacts of DBPs in drinking water? Bladder cancer has been the most consistent finding from epidemiologic studies in North America and Europe and the possibility that chlorinated drinking water contributes an increased risk of bladder cancer remains a viable hypothesis. Despite some recent improvements in exposure assessments to focus on inhalation and dermal exposures rather than ingestion, no causal agent with sufficient carcinogenic potency has been identified, nor has a mechanistic model been validated. Consequently, a sensible precautionary approach to managing DBPs remains the only viable option based on four decades of evidence.