Therapeutic proteins and peptides have revolutionized treatment for a number of diseases, and the expected increase in macromolecule-based therapies brings a new set of challenges for the pharmaceutics field. Due to their poor stability, large molecular weight, and poor transport properties, therapeutic proteins and peptides are predominantly limited to parenteral administration. The short serum half-lives typically require frequent injections to maintain an effective dose, and patient compliance is a growing issue as therapeutic protein treatments become more widely available. A number of studies have underscored the relationship of subcutaneous injections with patient non-adherence, estimating that over half of insulin-dependent adults intentionally skip injections. The development of oral formulations has the potential to address some issues associated with non-adherence including the interference with daily activities, embarrassment, and injection pain. Oral delivery can also help to eliminate the adverse effects and scar tissue buildup associated with repeated injections. However, there are several major challenges associated with oral delivery of proteins and peptides, such as the instability in the gastrointestinal (GI) tract, low permeability, and a narrow absorption window in the intestine. This review provides a detailed overview of the oral delivery route and associated challenges. Recent advances in formulation and drug delivery technologies to enhance bioavailability are discussed, including the co-administration of compounds to alter conditions in the GI tract, the modification of the macromolecule physicochemical properties, and the use of improved targeted and controlled release carriers.