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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2006.10.016 Byline: Erin E. Matthews (1)(2), Manuela Zoonens (2), Donald M. Engelman (2) Abstract: Studying how protein transmembrane domains transmit signals across membranes is beset by unique challenges. Here, we discuss the circumstances that have led to success and reflect on what has been learned from these examples. Such efforts suggest that some of the most interesting properties of transmembrane helix interactions may be the least amenable to study by current techniques. Author Affiliation: (1) Department of Chemistry, Yale University, 266 Whitney Avenue, New Haven, CT 06520, USA (2) Department of Molecular Biophysics and Biochemistry, Yale University, 266 Whitney Avenue, New Haven, CT 06520, USA