Oral delivery of peptide therapeutics as a convenient alternate to injections has been an area of research for the pharmaceutical scientific community for the last several decades. However, systemic delivery of therapeutic peptides via the oral route has been a daunting task due to the low pH denaturation of the peptides in the stomach, enzymatic instability, and poor transport across the tight junctions resulting in very low bioavailability. The low bioavailability is accompanied by large intra- and inter-subject variability leading to translational issues, preventing the development of successful peptide therapeutics. The inter-subject variability leads to large differences in pharmacologic responses in individuals and thus the dose required to produce therapeutic effect could vary between individuals making the development of drug product a very difficult task. A substantial amount of research has been (and continues to be) performed with a focus on getting acceptable absorption and reproducible results. Nonetheless, the high variability and low bioavailability during oral administration of peptides is still a work in progress and under-explored in a systematic way. While there are several review articles and scattered publications that discuss potential technologies for oral peptide delivery, a detailed look into the physiological challenges and absorption barriers which are a hindrance to successful clinical translation, is lacking. Herein, we have analyzed the physiological barriers within the gastrointestinal (GI) tract that are the root causes for the low bioavailability and high variability of oral delivery of peptides in humans. In particular, we have taken a detailed look at the key influencing factors such as the nature of various GI tract parameters, components of the GI tract that influences the uptake, site of absorption, pH of the gastric and intestinal compartments, food effect, and role of peptidases in affecting oral peptide absorption. Lack of in vitro - in vivo correlations and variability in animal models have also been highlighted as key impediments in understanding the challenges. The unique perspective presented herein for overcoming the physiological absorption barriers, will offer better developability approaches and will positively impact clinical translation of future oral peptide therapeutics. A deep understanding of these effects are vital, given the emergence of microbiome and oral biologic drug delivery that are fast emerging as the next wave of personalized patient centric therapies. Display omitted