Beautiful examples from the study of regulation in prokaryotes have clearly demonstrated the exquisite power of genetics to unravel complex biological problems. 1 It is our belief that an answer to the various questions raised in higher organisms about cell architecture, gene regulation, transmembrane signaling, etc. could greatly benefit from genetic approaches. However, enthusiasm of scientists for somatic cell genetics has been somewhat hampered because these techniques often appear to lack specificity and are time consuming. With the example of the Na+/H+ antiporter described in this chapter, we would like to illustrate, if necessary, that genetics of mammalian cells in culture can be very valuable in learning about the structure and function of membrane proteins expressed in minute amounts. Our first objective, in developing the genetics of the Na+/H+ antiporter, was to isolate fibroblast mutants completely lacking the antiport activity. These mutants were expected to be most useful in assessing the physiological role of this transporter and in evaluating the role of intracellular pH in growth-factor action. Our second objective was to exploit the advances in gene transfer and gene amplification techniques to gain access to the structure of the antiporter molecule through its molecular cloning. This objective having not yet been completely achieved, we shall present our most recent results.