Despite their very small genomes mycoplasmas are successful pathogens of man and a wide range of animal hosts. Because of the lack of effective therapeutics and vaccines, mycoplasma diseases continue to be a significant problem for public health as well as livestock production with major socio-economic consequences worldwide. Recent outbreaks and epidemiological studies predict that the incidence of human and animal mycoplasma diseases might increase which indicates the urgent need to develop new approaches for prevention and therapy. Development of such reagents, however, requires a solid understanding of the molecular biology of mycoplasma infections. Knowledge in this field has considerably increased during the past decade since new techniques have been developed and adapted to mycoplasmas that allow these organisms to be studied at the molecular level. Research on the two human pathogens Mycoplasma pneumoniae and Mycoplasma genitalium of which the genome sequences have recently been completed as well as the substantial number of studies carried out on the AIDS-associated mycoplasmas, Mycoplasma penetrans and Mycoplasma fermentans, has led the way, but a number of animal mycoplasmas are becoming increasingly appreciated as models for the study of the molecular basis of mycoplasma diseases. This review summarizes and highlights some of the recent findings concerning the molecular interactions that occur between pathogenic mycoplasmas and their hosts, both the common strategies as well as some unique approaches evolved by particular mycoplasma pathogens, including adherence to and uptake into non-phagocytic host cells, as well as mechanisms of escaping the host immune system.