The rise of so-called “safe harbors” – conditions that, when satisfied, trigger a presumption of legality – is among the most prominent features of the evolution of antitrust law in the modern era. The emergence of antitrust safe harbors occurred quickly and is attributable to significant contributions from the Supreme Court, lower courts, and the federal antitrust agencies. The recent and ongoing weakening and disappearance of safe harbors from the antitrust landscape has been less well recognized. We explain the causes and consequences of the rise and fall of antitrust safe harbors. We argue that the disappearance of safe harbors is not explained by reversals in any of the factors – a shift in economic analysis of legal rules, economic theory, empirical evidence, or the influence of particular judicial appointments – that led to the original rise in safe harbors. Preliminary evidence suggests that other forces are at work, including but not limited to, changes over time in both partisanship and preferences for standards over rules at the FTC. If we are correct that the current and ongoing shift away from safe harbors at the agencies and in the courts is the result of systematic changes, understanding its causes will be critical to identifying its implications for agencies, courts, and practitioners moving forward.