The present paper provides an overview of key coupled thermo-hydro-mechanical (THM) processes in clay formations that would result from the development of a high-level radioactive waste repository. Here, in this paper, clay formations include plastic clay such as the Boom Clay of Belgium, as well as more indurated clay such as the Callovo-Oxfordian and Upper Toarcian of France and Opalinus Clay of Switzerland. First, we briefly introduce and describe four major Underground Research Laboratories (URLs) that have been devoted to clay repository research over the last few decades. Much of the research results in this area have been gained through investigations in these URLs and their supporting laboratory and modeling research activities. Then, the basic elements in the development of a waste repository in clays are presented in terms of four distinct stages in repository development. For each of these four stages, key processes and outstanding issues are discussed. A summary of the important areas of research needs and some general remarks then conclude this paper.