In the last 50 years, changes in cultural and scientific realities and customs have resulted in a worldwide epidemic of sexually transmitted diseases (STD). This is a multi-factorial problem resulting in part from: 1) an increased permissiveness in sexual attitudes in the Western world that results in earlier onset of intercourse and increased numbers of partners and types of sex acts; 2) a global transportation network that facilitates contacts and interactions between urban and rural areas as well as between countries resulting in migration and spread of infections; 3) an emergence of new and mutated forms of pathogens with increased capabilities to cause infections and for which there are no available vaccines or therapies; and, 4) at risk populations in developing countries who are susceptible to these pathogens while having societal infrastructures that lack basic health education and proper access to healthcare. Overwhelming examples of increasing and emerging STD pathogens exist in the early twenty-first century. These include human immunodeficiency virus type 1 (HIV-1), the causative agent of acquired immunodeficiency syndrome (AIDS), with over 42 million current cases of infection, 20 million deaths to date, and an estimated 500,000 deaths per year; human papillomavirus (HPV) infections, the causative agents of genital warts and cervical cancer, with approximately 1 in 4 women harboring virus DNA in genital epithelium, 1-3 percent of women showing symptoms of infection and 250,000 deaths per year in women worldwide from cervical cancer; and numerous others. Topical microbicides have been proposed as agents to break the chain of transmission in these infections by providing chemical, biological, and/or physical barriers to infection by blocking and/or inactivating pathogens at the mucosal surface where infection can occur. For many sexually transmitted infections, vaccines do not exist, and therapeutic agents are only partially effective, expensive, and difficult to distribute. In addition, female partners in many relationships do not control pregnancy or STD risk and may benefit from discrete methods, other than condoms, that would provide protection. Thus, microbicides should be valuable additions to preventing these diseases if they can be shown effective. Currently, 62 microbicides are in development with 6 entering Phase III clinical trials, 11 entering Phase I clinical trials, and 44 in pre-clinical development. In this review, we will describe many of the principles of microbicide mechanisms and give examples of major types of microbicides and their actions. Space precludes a complete description of all of the agents and their mechanisms of action. We will also put forth the argument for alkyl sulfate microbicides, including sodium dodecyl sulfate (SDS), agents that are in active development in our laboratories.