As masters of genome-wide regulation, miRNAs represent a key component in the complex architecture of cellular processes. Over the last decade, it has become increasingly apparent that miRNAs have many important roles in the development of disease and cancer. Recently, however, their role in viral and bacterial gene regulation as well as host gene regulation during disease progression has become a field of interest. Due to their small size, miRNAs are the ideal mechanism for bacteria and viruses that have limited room in their genomes, as a single miRNA can target up to ~30 genes. Currently, only a limited number of miRNA and miRNA-like RNAs have been found in bacteria and viruses, a number that is sure to increase rapidly in the future. The interactions of these small noncoding RNAs in such primitive species have wide-reaching effects, from increasing viral and bacterial proliferation, better responses to stress, increased virulence, to manipulation of host immune responses to provide a more ideal environment for these pathogens to thrive. Here, we explore those roles to obtain a better grasp of just how complicated disease truly is.