The pharmaceutical relevance of proton-coupled peptide transporters is currently under intense investigation in many laboratories. Studies have shown that these membrane proteins, expressed in intestine, kidney, choroid plexus and other tissues, accept many peptidomimetic drugs and prodrugs as substrates. The focus of this review is on the interaction of beta-lactam antibiotics, angiotensin-converting enzyme inhibitors, sartans and other drugs with PEPT1 and PEPT2. The article highlights progress made in recent years and the most expedient techniques that have been or are being employed. It also emphasizes the opportunities in rational drug design that are of highest priority and the pitfalls that must be avoided. Finally, an instructional flowchart that might be used to identify a peptide transporter substrate is proposed.