The U.S. opioid crisis has been defined by its pushing of regulatory agencies to their limits, and filling regulatory gaps with product liability litigation that, in the end, also struggled to deal with the myriad challenges posed by opioids. Accordingly, this chapter explored the fundamental tension between ex ante regulation and ex post litigation in the handling of the opioid crisis, adopting a comparative governance approach that highlighted the pros and cons of regulation versus litigation in governing complex externalities and transactions, such as those associated with high-risk medical products generally and opioids specifically. The opioid crisis has highlighted some important limitations of the existing prescription drug regulatory apparatus, including excessive bureaucracy and disproportionate attention on pre-market approval versus post-market surveillance. Given the importance of the laboratory of the “real world” in improving the understanding of the effectiveness and risks of medical products, it makes sense that the strengthening of post-market surveillance should be part of any FDA and DEA reform efforts. However, as the discussion in this chapter implies, there may be good reasons to assume that, for products with particularly high risks, the probability of post-market litigation should be considered in risk-benefit analysis.