Do entrepreneurial ventures involve risk? The quick answer to this question is “well, of course they do!” And there is no shortage of supportive data. For example, the US Panel Studies of Entrepreneurial Dynamics (PSED) Gartner et al., 2004; Reynolds and Curtin, 2009, 2011) shows that as many as 72 months after a business-organizing venture begins, only some 30 percent of efforts have produced new firms. Spending six years trying to organize a company “risks” at least the time and opportunity cost; selling a company for less than the venture-capital raised “risks” the wealth of the investors. But there are at least two important differences. First, investors can take a portfolio approach to try to balance risks and rewards. Individuals, however, typically start only one enterprise at a time, so they stand to lose “all,” not just “some.” Second, investment decisions made by angels or venture capitalists are typically collective decisions, involving the best guesses of multiple brains. By contract, business-organizing decisions are typically made by a single brain. At the present stage of theory and research, the single-brain decisions have been most heavily studied by the methods of neuroscience. Consequently, this chapter restricts its focus to the judgments of risk made by individual entrepreneurs. When the goal is to examine the brain correlates of variations in risk judgments, restricting the investigation to an individual person is merely the beginning. At least four other design elements need to be considered for the final answers to be clear: (1) there must be a conceptual analysis that distinguishes one sort of risk from others; (2) the research designs chosen must maximize the opportunity to obtain meaningful results; (3) the concepts selected for testing must be operationalized unambiguously; (4) potential methodological confounding must be avoided. The present chapter is organized to address each of these concerns in turn to identify practices that might better enable researchers to understand the cognitive neuroscience of entrepreneurial risk.