A considerable number of infectious diseases involve multiple microbial species coexisting and interacting in a host. Only recently however the impact of these polymicrobial diseases has been appreciated and investigated. Often, the causative microbial species are embedded in an extracellular matrix forming biofilms, a form of existence that offers protection against chemotherapeutic agents and host immune defenses. Therefore, recent efforts have focused on developing novel therapeutic strategies targeting biofilm-associated polymicrobial infections, a task that has proved to be challenging. One promising approach to inhibit the development of such complex infections is to impede the interactions between the microbial species via inhibition of adhesion. To that end, studies have focused on identifying specific cell wall adhesins and receptors involved in the interactions between the various bacterial species and the most pathogenic human fungal species Candida albicans. This review highlights the important findings from these studies and describes the available tools and techniques that have provided insights into the role of secreted molecules orchestrating microbial interactions in biofilms. Specifically, we focus on the interactions that take place in oral biofilms and the implications of these interactions on oral health and therapeutic strategies.