Few drug development surprises can be as devastating as serious toxicity problems that only show up under a combination of conditions as idiosyncratic toxicity. Because of the role of variations in human drug metabolizing enzymes there is likely to be little or no evidence of such problems during pre-clinical safety studies. Such problems are also unlikely to show up in all but the largest clinical trials, but if the side effects are lethal, it can result in product withdrawal. What strategies are available or under development to anticipate such problems, and when do such efforts justify their costs? What lessons can be learned from case studies of recalled products, including best practices for minimizing economic and reputation impact?