It is well acknowledged in the Mycoplasmology community that immunopathology plays a large role in the pathogenesis of many Mycoplasma species. Indeed, the most common manifestations of disease caused by Mycoplasma pathogens are those induced by exuberant immune cell infiltration in the target tissue (i.e. Mastitis, , Tracheitis, Synovitis, Bronchitis, Mucositis, and Pneumonia). Despite their critical role in Mycoplasma pathogenesis, sufficient consensus regarding host immune responses that are maladaptive or protective does not exist in the community. This proves detrimental when considering rational design of vaccine candidates; many of which fail to show sufficient protective efficacy in the field due to eliciting insufficient protective immunity. Contributing largely to the confusion over which responses are protective vs maladaptive, is the lack of standardized methodology for assessing host immune responses to vaccination or infection with Mycoplasma pathogens. At present, some Mycoplasmologists report immunological data conducted solely through in vitro stimulation of leukocytic cell lines, others report responses from ex vivo stimulation of peripheral blood mononuclear cells, and few report immunological responses from the primary site of infection. Often, these reports are also not appropriately contextualized, and ignore the effect that immune compartmentalization plays in the responses that are being observed. As such, confusion results from studies reporting seemingly conflicting results. While host species differences do exist, there are a myriad of commonalities observed during Mycoplasma infection, regardless of the host species or Mycoplasma pathogen being studied. A comparative approach to studying Mycoplasma infections and interactions with the immune system across di􏰀erent species can reveal universal strategies employed by Mycoplasma pathogens and identify potential targets for therapeutic interventions.