Polymicrobial infections are commonly found in tilapia farming as fish are normally exposed to rich communities of bacteria, fungi, viruses, and parasites. However, little is currently known about multiple infection patterns affecting wild and farmed tilapia. Generally, polymicrobial infection patterns involve heterogeneous infectious agents simultaneously or sequentially interacting with susceptible hosts. They can alter pathogenesis, eliciting synergistic or antagonistic effects and complex clinical symptoms when compared to single infection patterns. The outcomes of microbial interference modulate the host immune response with repercussions on the efficacy of treatments and prevention strategies. Linked to the fast growth of tilapia aquaculture and to changing environmental conditions, the study of polymicrobial disease patterns, representing a so far neglected concept, is rapidly attracting the interest of aquatic animal health scientists, and is becoming an emerging and highly researched area. The aim of this talk is to broaden our understanding of how polymicrobial infections affect the host, and how they cause disease when infecting their hosts in an array of aquatic environments and farming conditions, either in natural or artificial systems. Understanding these complex interactions will facilitate disease control and mitigation to reduce the negative impact of polymicrobial infections mainly small-scale tilapia farmers.