Polybacterial diseases involve multiple organisms that act collectively to facilitate disease progression. Although this phenomenon was highlighted early in the 20th century, recent technological advances in diagnostics have led to the appreciation that many infections are far more complex than originally believed. Furthermore, it is apparent that although most treatments focus on the dominant bacterial species in an infection, other microbes, including commensals, can have a profound impact on both the response to therapy and virulence. Very little is known about the molecular mechanisms that underpin interactions between bacteria during such infections. Here, we discuss recent studies identifying and characterizing mechanisms of bacterial interaction and the biological processes they govern during certain diseases. We also highlight how possible strategies for targeting these interbacterial interactions may afford a route towards development of new therapies, with consequences for disease control.