Detailed analysis of molecular interactions is the key to understanding the mechanism of signal transduction and its intervention by inhibitory compounds. In this chapter, we shall review and discuss the application of isotope edited FTIR spectroscopy to the investigation of protein-protein interactions. Recently we have employed this technique to investigate the molecular interactions of granulocyte colony stimulating factor (G-CSF) with the isolated immunoglobular domain (Ig) of its receptor [1,2]. To resolve the amide I' band overlap of G-CSF with that of the receptor in the FTIR spectrum of the complex, ¹³C/¹⁵N uniformly labeled G-CSF was prepared for this study. By comparing the FTIR spectra of the isotope-labeled G-CSF and the isolated receptor with that of the complex, we have provided spectral evidence that the AB loop region involving the unique 310 helix segment of G-CSF likely undergoes a conformational change to a regular α-helix upon binding to the receptor domain. The IR data also indicate significant conformational changes involving β-turns and irregular structures in the Ig domain of the receptor in the complex. Furthermore, FTIR spectra of G-CSF, the receptor, and their complex demonstrate clearly that protein conformations of both G-CSF and the receptor are dramatically stabilized by complex formation. Together, the current data strongly suggest that the AB loop region including the 310 helix interacts specifically with the immunoglobulin-like domain of the receptor, which may play a role in receptor dimerization. This conclusion supports the structural model recently proposed by Layton and co-workers [3]. In summary, this work demonstrates that specific structural information of protein-protein complexes can be obtained by employing isotope-edited FTIR spectroscopy.