Clinical decision support systems (CDSSs) symbolize a significant transformation in healthcare delivery. CDSS enhances healthcare delivery by enabling personnel in medical institutions to handle complex decision-making processes with great speed and high accuracy. Decision support systems are developed using a knowledge-driven or data-driven approach, although both approaches seem to complement each other. For instance, while data-driven is an objective approach, the knowledge-driven approach is subjective. The objective of the chapter is to elaborate on the integration of data-driven and knowledge-driven methodologies for clinical decision support systems. An overview of data-driven and knowledge-driven approaches is presented with a review of both current and dated literature on the subject with numerous viewpoints to support the discussion. Based on the findings, a promising methodology is proposed that integrates data-driven and knowledge-driven approaches and is believed to overcome the challenges of the individual approaches.