Orally administered devices could enable the systemic uptake of biologic therapeutics by engineering around the physiological barriers present in the gastrointestinal (GI) tract. Such devices aim to shield cargo from degradative enzymes and increase the diffusion rate of medication through the GI mucosa. In order to achieve clinical relevance, these designs must significantly increase systemic drug bioavailability, deliver a clinically relevant dose and remain safe when taken frequently. Such an achievement stands to reduce our dependence on needle injections, potentially increasing patient adherence and reducing needle-associated complications. Here we discuss the physical and chemical constraints imposed by the GI organs and use these to develop a set of boundary conditions on oral device designs for the delivery of macromolecules. We critically examine how device size affects the rate of intestinal obstruction and hinders the loading capacity of poorly soluble protein drugs. We then discuss how current orally administered devices could solve the problem of tissue permeation and conclude that these physical methods stand to provide an efficacious set of alternatives to the classic hypodermic needle.