Over the past two decades, innovations in small-animal positron emission tomography (PET) have reached an impressive level, which has brought countless opportunities to explore the major puzzles in biomedical research. It is a given that pairing information coming from different imaging modalities renders unprecedented knowledge and provides a great insight into various facets of biological systems, such as anatomy, function, physiology, and metabolism in animal models of human diseases, which are difficult to be beaten by standalone PET scanners. The development of bimodal and tri-modal imaging platforms with advanced software solutions dedicated for quantitative studies in small-animals has spurred academic and industrial interest. However, it is undisputed that the potential success of these scanners in filling the translational gap between human and animal findings, hinges to a great extent upon optimization and standardization of relevant parameters and acquisition protocols, which is often overlooked.