Mycoplasmas contain the smallest genomes and are the smallest known free-living organisms, yet little is known about the molecular details of their pathogenic mechanisms. This review focuses on pathogens of production animals, but related species colonize and cause disease in humans, fish and other animals, plants and insects. The general lack of genetic tools and the inability to apply the few that are available to some mycoplasma-host systems has hindered studies of this nature. During the last decade, which was characterized by unparalleled advances in the understanding of bacterial virulence, studies of mycoplasma pathogenesis has languished behind other experimental systems. The one exception has been studies on mycoplasma antigenic variation. The explosion of studies in this area has been due primarily to the fact that they can be performed in vitro without genetic tools and with simple well developed biochemical approaches. Not withstanding that antigenic variation may play an important role in disease, there have been few studies establishing the importance of this phenomenon in vivo for a variety of reasons. The same is true for cell invasion as it has been defined in cell culture systems, which if it occurs in vivo may change the way we think about mycoplasma disease. These advances give insight to an extraordinary group of organisms that interact with their hosts in unique and intriguing ways.