Since the discovery of HIV at the beginning of the 1980s, numerous efforts have been devoted to the search of an efficient vaccine. There are at least 25 drugs available for HIV treatment, but no cure is available. The observation that therapy for HIV disease is life long and that these drugs are associated with a number of side effects underlines the need for approaches aimed at preventing rather than treating infection. Additionally, the economic burden of treatment for the HIV infection occupies an increasing share of healthcare expenditure, making current practices likely to become difficult to sustain in the long run. Unfortunately, no effective vaccine for this disease is foreseeable in the near future. Microbicides could be an alternate way to build preventative approaches to HIV infection. Strategies based on preventing the virus from reaching its target cells seem to have some room for development and application. In this review we explore the state-of-the-art of available microbicides, focusing on HIV entry inhibitors. In addition, we discuss new compounds that show anti-HIV activity, which could be effective candidates.