Display omitted •Overview of colonic drug delivery systems.•Potential for local and systemic delivery.•Key focus on metabolic activity of the colonic microbiota.•Challenges of microbiota-sensitive natural polysaccharides.•Laying special emphasize on oral dosage forms of chemical and biological drugs. Colon targeting is an ongoing challenge, particularly for the oral administration of biological drugs or local treatment of inflammatory bowel disease (IBD). In both cases, drugs are known to be sensitive to the harsh conditions of the upper gastrointestinal tract (GIT) and, thus, must be protected. Here, we provide an overview of recently developed colonic site-specific drug delivery systems based on microbiota sensitivity of natural polysaccharides. Polysaccharides act as a substrate for enzymes secreted by the microbiota located in the distal part of GIT. The dosage form is adapted to the pathophysiology of the patient and, thus, a combination of bacteria-sensitive and time-controlled release or pH-dependent systems can be used for delivery.