Colon-specific drug delivery systems have recently gained enormous importance for the delivery of a variety of therapeutic compounds. To deliver a drug molecule intact to the colon, the delivery system must pass through the upper part of the gastrointestinal tract without being degraded. Researchers have attempted various approaches in the formulation of colon-specific drug delivery systems. Among them, the most promising are the microbially and/or enzymatically driven drug delivery systems, consisting of biodegradable polymers (polysaccharides) and prodrugs. The major advantage of the microbially and/or enzymatically driven colon-specific drug delivery systems is that they can sense the arrival of the formulation in the colon and release the drug upon activation. This review familiarizes readers with the recent advancements in microbially and/or enzymatically driven colon-specific drug delivery systems, along with their in vitro and in vivo evaluation.