The necessity and advantages of colon-specific drug delivery systems have been well recognized and documented. In the past, the primary approaches to obtain colon-specific delivery achieved limited success and included prodrugs, pH- and time-dependent systems, and microflora-activated systems. Precise colon drug delivery requires that the triggering mechanism in the delivery system only respond to the physiological conditions particular to the colon. Hence, continuous efforts have been focused on designing colon-specific delivery systems with improved site specificity and versatile drug release kinetics to accommodate different therapeutic needs. Among the systems developed most recently for colon-specific delivery, four systems were unique in terms of achieving in vivo site specificity, design rationale, and feasibility of the manufacturing process (pressure-controlled colon delivery capsules (PCDCs), CODES, colonic drug delivery system based on pectin and galactomannan coating, and Azo hydrogels). The focus of this review is to provide detailed descriptions of the four systems, in particular, and in vitro/in vivo evaluation of colon-specific drug delivery systems, in general.