Purpose of Review Mycoplasma, economically important pathogens in livestock, often establishes immunologically complex persistent infections that drive their pathogenesis and complicate prophylaxis and therapy of the caused diseases. In this review, we summarize some of the recent findings concerning cellular and molecular persistence mechanisms related to the pathogenesis of mycoplasma infections in livestock. Recent Findings Data from recent studies prove several mechanisms including intracellular lifestyle, immune dysregulation, and autoimmunity as well as microcolony and biofilm formation and apoptosis of different host cell types as important persistence mechanisms in several clinically significant Mycoplasma species, i.e., M. bovis, M. gallisepticum, M. hyopneumoniae, and M. suis. Summary Evasion of the immune system and the establishment of persistent infections are key features in the pathogenesis of livestock mycoplasmas. In-depth knowledge of the underlying mechanisms will provide the basis for the development of therapy and prophylaxis strategies against mycoplasma infections.