In the past two decades, there has been growing interest in the process of clinical decision making (CDM). Importantly, a strong interest has flourished in the process of diagnosis, particularly its failure rate. Two major strategies have been proposed to ameliorate diagnostic failure: minimizing system error and strategies to promote optimal clinical decision making. Many health care environments are not optimal. A variety of factors have been identified that influence the safe operation of the system, and clinicians need to be cognizant of them. In this chapter, a number of strategies are reviewed to optimize the CDM that occurs within the system, including the promotion of rationality, metacognition, thinking skills, flexibility, innovation and creativity in thinking, lateral thinking, cognitive bias mitigation, the incorporation of artificial intelligence, and distributed cognition. Instead of assuming that competence in CDM will be tacitly acquired in the course of medical education, clinicians need to advocate for explicit interventions that are known to raise the caliber of CDM.