The concept of acceptability involves a complex set of individual, couple and socio-cultural factors. Within a specific focus on microbicides, this article sets forth the relevant behavioral issues demanding attention as scientists and product developers strive to identify microbicides that will be used in a sustained, long-term fashion to prevent HIV/AIDS. The paper re-conceptualizes long-term acceptability within the ARRM framework, reviews the basic issues and research related to microbicide acceptability, discusses couple relationships (especially the nature of intimate relationships), and identifies related gender and power factors. The importance of the cultural context within various international settings pervades all of these issues. Finally, a set of challenges is discussed for those contemplating such research.