Health, safety, and environmental regulation in the United States are saturated with risk thinking. It was not always so, and it may not be so in the future. But today, the formal, quantitative approach to risk provides much of the basis for regulation in these fields, a development that seems quite natural, even necessary. This particular approach, while it drew on conceptual and technical developments that had been underway for decades, achieved prominence during a relatively short timeframe; roughly, between the mid-1970s and the early 1980s — a time of hard looks and regulatory reform. Prior to this time, formal conceptions of risk were rarely invoked in the effort to regulate the increasingly complex set of hazards associated with industrial society and quantitative risk assessment was considered too uncertain to serve as a basis for regulatory decision making. With few exceptions, safety, hazard, and endangerment provided the dominant framings, drawing on different conceptual and normative tendencies and leading to different regulatory outcomes. This Article investigates the emergence and development of formal approaches to risk in health, safety, and environmental law during the twentieth century. It focuses specifically on the concepts, tools, and practices that have underwritten risk thinking in these fields, developing a perspective on health, safety, and environmental regulation that seeks to historicize risk and situate the contemporary debate regarding the merits of risk versus precaution in its proper historical context. In doing so, the Article demonstrates how both approaches struggled to address the much more vast and complicated world of potential environmental harm brought into view as a result of substantial advances in analytical techniques during the 1960s and early 1970s, thereby revealing the contours of a more fundamental clash over environmental law’s distinctive problem of knowledge. The Article covers the formative period from the New Deal through the 1970s, showing how efforts to operationalize safety in the middle decades of the twentieth century led to many of the foundational concepts and techniques that would structure risk thinking in subsequent decades, highlighting the critical role of analytical advances in pushing toward a re-definition of safety as acceptable risk and a corresponding move toward quantitative risk assessment, and revealing how earlier precautionary impulses were ultimately subsumed under an emerging administrative law of risk.