Study of drug resistance began in the late 1940's, and recognition that altered membrane transport of drug was often related to cellular drug resistance followed approximately 20 years later. Identification and isolation of specific membrane proteins that influence this altered drug transport began in the 1970's and is a major ongoing endeavor to this day. In this article, we refer to such proteins as “drug resistance associated membrane proteins,” or “DRAMPs.” In over 40 years, dozens of books and tens of thousands of research articles have asked how drug resistance is mediated by various DRAMPs. By comparison, relatively few studies have probed the normal physiological function of these proteins. In many cases, deletion of the gene encoding a DRAMP is not lethal, showing that the function of the protein is non-essential, but in some cases (e.g., PfCRT protein involved in antimalarial drug resistance) deletion is not possible, suggesting an essential function. For some DRAMPs a clear role in specific cell biological processes has been established (e.g., Ishikawa et al., 1997; Jin et al., 2002; Baugh et al., 2012; Quazi and Molday, 2013), but in most cases we are no closer to a detailed molecular definition of the physiologic function of DRAMPs than we were when these proteins were first discovered. When they are involved in drug resistance, DRAMPs are often either mutated or overexpressed, and in some cases both. Quantitative comparison between wild type and mutant isoforms of DRAMPs, or between normal and higher levels, is often quite difficult for a variety of technical reasons, and this has probably slowed elucidation of their physiologic function.