With the advent of new technologies and radical growth in the field of biotechnology, dozens of protein and peptide drugs have been marketed. However, there are several challenges for successful delivery of such molecules. A number of routes have been used for the delivery of these fragile molecules by exploring various novel delivery technologies, including microspheres, liposomes, gel spheres, nano-spheres, niosomes, microemulsions, use of permeation enhancers, use of protease inhibitors, etc. But the route that has attracted the attention of worldwide drug delivery scientists is the oral route due to its various advantages. Even though the proteolytic activity is higher in a few segments of the gastrointestinal tract (GIT), this route has certain segments that have lower proteolytic activity, for example, the colon. The colon has captured attention as a site for the delivery of these molecules because of its greater responsiveness to absorption enhancers, protease inhibitors, and novel bioadhesive and biodegradable polymers. Although the success rate of these approaches, when used alone is pretty low, when used in combinations, these agents have demonstrated wonders in increasing the drug bioavailability. This review focuses on the challenges, pharmaceutical concepts, and approaches involved in the delivery of these fragile molecules, specifically to the colon. This review also includes studies conducted on colonic targeting of such drugs. Further studies may lead to improvements in therapy using protein/peptide drugs and refinements in the technology of colon-specific drug delivery.