Recent advances in the fields of molecular biology and biotechnology have allowed for the large-scale production and subsequent exploitation of the therapeutic potential of protein- and peptide-based drugs. The facilitation of delivery of this class of drugs must be tailored to meet the requirements and often the limitations dictated by the route of delivery chosen. The aim of this review is to comprehensively discuss several routes of drug delivery, detailing the uses and exploitation of each, from origins to present day approaches. Specific reference is made to the compatibility or incompatibility of each approach in the facilitation of the delivery of drugs of protein origin. Additionally, the physiological nature of the delivery route and the inherent physiological obstacles that must be considered when determining the most suitable approach to drug design and delivery enhancement are also addressed. Examples of novel protein-based drug designs and delivery methodologies that illustrate such enhancement strategies are explored.