A range of cellular signaling mechanisms are controlled by highly specific protein-protein binding, which controls both protein function and protein distribution. The presentation focuses on the use of two complementary approaches to interrogate these mechanisms at the protein and cellular levels, the expression of recombinant proteins and protein binding domains using bacterial protein expression for biochemical studies and using mammalian protein expression for cell biology studies. Examples from neuroscience and ion channel physiology are being discussed and utilized to illustrate the impact of transgenic approaches when integrated with functional assays. In addition, the presentation includes clinical rationales for experimental design underlying the development of recombinant transgenic proteins and protein fragments to probe cellular signaling mechanisms. Conversely, the impact of the identification of such mechanism on preclinical research and subsequent therapy development is being discussed.