Natural and agricultural ecosystems harbor a wide variety of microorganisms that play an integral role in plant health, crop productivity, and preservation of multiple ecosystem functions. Interactions within and among microbial communities are numerous and range from synergistic and mutualistic to antagonistic and parasitic. Antagonistic and parasitic interactions have been exploited in the area of biological control of plant pathogenic microorganisms. To date, biocontrol is typically viewed from the perspective of how antagonists affect pathogens. This review examines the other face of this interaction: how plant pathogens respond to antagonists and how this can affect the efficacy of biocontrol. Just as microbial antagonists utilize a diverse arsenal of mechanisms to dominate interactions with pathogens, pathogens have surprisingly diverse responses to counteract antagonism. These responses include detoxification, repression of biosynthetic genes involved in biocontrol, active efflux of antibiotics, and antibiotic resistance. Understanding pathogen self-defense mechanisms for coping with antagonist assault provides a novel approach to improving the durability of biologically based disease control strategies and has implications for the deployment of transgenes (microorganisms or plants).