Drug discovery is inherently very risky. The management of these risks can enable the effective use of limited human and monetary resources. A careful attention to risk management in early discovery is especially important given that what happens in the early phases of a project may dictate the course of a research program for months or years. Risk management in early discovery starts with high-level managerial concerns: careful project selection, sufficient staffing and funding, and access to the appropriate instrumentation and tools. Herein we describe the operational elements of risk management that range from the very broad to the extremely specific. These elements have as their base an embedded culture of risk management that extends down to the experiment level, and project ownership in which all researchers anticipate risk, but are not paralyzed by it. In our model, on this base of culture stand the four pillars of early discovery risk management: right libraries, right assays, right series, and right structure–activity relationships. Appropriate attention to these considerations can decrease the risks inherent in early discovery medicinal chemistry, thereby potentially increasing the return on the investment of necessarily finite resources.