This chapter provides a comprehensive exploration of Clinical Decision Support Systems (CDSSs), with a particular emphasis on diagnostic CDSS. The primary aim is to delineate the various classifications and functionalities of CDSSs while highlighting their pivotal role in modern health care. By exploring the methodologies underlying diagnostic CDSS—knowledge-based and non-knowledge-based—this chapter emphasizes their contributions to clinical workflows, their strengths and limitations, and their potential to improve diagnostic accuracy, efficiency, and patient outcomes. Additionally, specialized diagnostic CDSS applications in laboratory, imaging, and pathology contexts are explored, illustrating how these systems integrate advanced technologies to transform the diagnostic landscape.