This chapter defines risk-taking in organic synthesis as the deliberate pursuit of strategies that do not have near neighbors in the chemical literature. In these ventures into the unknown, chemical behavior can be difficult to predict. The literature of organic chemistry is replete with examples of powerful, bond-forming strategies that had little or no precedent when they were developed. This essay addresses some of those examples in an effort to demonstrate the merits of creative risk-taking in the planning and execution of organic syntheses.