The effective oral drug delivery in animals and humans requires an understanding of their unique gastrointestinal tract (GIT) physiology and biochemical regulators. Oral drugs rely on how effectively absorbed through the intestinal wall and come into systemic circulation. Absorption is hindered by various factors within the enteric epithelium, such as efflux transporters, enzymatic degradation, tight junctions in addition to intestinal linings, and first-pass hepatic metabolism. Factor related to the drugs are hydrophilicity or lipophilicity, high molecular weight, or substrates of efflux transporters, another challenging limiting factor. Thus, careful designing of oral delivery systems is required in order to improve the systemic availability of drug by taking into various factors. The majority of drugs are taken orally, as this route is more convenient and practical, except in emergency and hospitalized conditions. Despite advancements in the pharmaceutical industry, orally administered drugs many times fail to produce the desired effect due to limiting factors of GIT. Here, we discussed the physiological and pharmacological aspects of the GIT. We also tried to discuss the challenges underlying in oral drug delivery and future strategy for improvement of drug delivery via the gastrointestinal tract.