Non-ionic surfactants have been proposed as dual action anti-viral and spermicidal agents to tackle viral infections, namely HIV. Given very promising in vitro results, nonoxynol-9 has been widely used. However, toxic effects were reported, paradoxically increasing the incidence of transmission of HIV/Sexually Transmitted Diseases in vivo. Thus, there has been a growing interest in identifying and evaluating a new generation of accessible and easy-to-use molecules with simultaneous spermicidal and microbicide action. Different biochemical compounds and mechanisms of action are currently being studied. This article reviews the diverse strategies and mechanisms of action of these novel compounds, as well the necessary systematic studies needed to evaluate their possible toxicity.