Abstract The aim of this article is to explore the complex forms of knowledge involved in diagnostic and interventional decision making by comparing the processes in medicine and nursing, including nurse practitioners. Many authors assert that the practice of clinical decision making involves the application of theoretical knowledge (acquired in the classroom and textbooks) as well as research evidence, upon concrete particular cases. This approach draws on various universal principles and algorithms to facilitate the task. On the other hand, others argue that this involves an intuitive form of judgement that is difficult to teach, one that is acquired principally through experience. In an exploration of these issues, this article consists of three sections. A clarification of terms commonly used when discussing decision making is provided in the first section. In the second section, an epistemological analysis of decision making is presented by examining several perspectives and comparing them for their use in the nursing and medical literature. Bunge's epistemological framework for decision making (based on scientific realism) is explored for its fit with the aims of medicine and nursing. The final section presents a discussion of knowledge utilization and decision making as it relates to the implications for the education and ongoing development of nurse practitioners. It is concluded that Donald Schön's conception of reflective practice best characterizes the skilful conduct of clinical decision making.