Radiolabeled peptide-based formulations are being evaluated for their application in oncological imaging and therapy using nuclear medicine techniques. A major breakthrough in the field was the discovery and identification of the G-protein coupled receptor superfamily that are overexpressed in a variety of human cancers. These receptors act as targets for endogenous compounds, often of peptidic nature, which can be radiolabeled and, therefore, could potentially be utilized as radiopharmaceuticals. This general strategy has proven successful for application in humans in only a few cases thus far. However, the use of more sophisticated structural methodology to enhance our understanding of the interactions between the receptor and the endogenous peptide or its analogs, and a more efficient preclinical evaluation process, may help to single out the most promising compounds for further development and eventual use in the clinical application of radiopharmaceuticals. This review analyzes current methods of approaching these key points. The rational process for developing peptide-based radiopharmaceuticals is presented, from the structural analysis of the peptide-receptor interaction for the identification and modeling of the peptide analogs to the synthesis, with an appropriate metal carrier, of compounds that mimic endogenous peptides. Finally, the in vitro and in vivo biological testing and evaluation in preclinical animal models is described. To render the entire process successful, expertise in different areas of drug development is indispensable.