Many physiological processes are controlled through the activation of G protein-coupled receptors (GPCRs) by regulatory peptides, making peptide GPCRs particularly useful targets for major human diseases such as diabetes and cancer. Peptide GPCRs are also being evaluated as next-generation targets for the development of novel anti-parasite agents and insecticides in veterinary medicine and agriculture. Resolution of crystal structures for several peptide GPCRs has advanced our understanding of peptide-receptor interactions and fuelled interest in correlating peptide heterogeneity with receptor binding properties. In this review, the knowledge of recently crystalized peptide-GPCR complexes, previously accumulated peptide structure-activity relationship (SAR) studies, receptor mutagenesis and sequence alignment are integrated to better understand peptide binding to the transmembrane cavity of Class A GPCRs. Using SAR data, we show that peptide Class A GPCRs can be divided into groups with distinct hydrophilic residues. These characteristic residues help explain the preference of a receptor to bind the C-terminal free carboxyl group, the C-terminal amidated group, or the N-terminal ammonium group of peptides. SIGNIFICANCE STATEMENT: The recent reporting of crystal structures of GPCRs bound to peptides allows structural diversity of peptide binding to be assessed for the first time. Furthermore, the structural data facilitates interpretation of peptide SAR studies and allows extrapolation of findings to related GPCRs. Thus, our polar residue analysis enables to group the peptide receptors highlighting conserved residues important for peptide binding. Despite a large heterogeneity in possible binding modes of peptides within GPCRs, some level of generalization of peptide binding can be established through the analysis of the peptide terminal end binding to the transmembrane helical cavity of GPCRs.