Mycoplasmas are most unusual self-replicating bacteria, possessing very small genomes, lacking cell wall components, requiring cholesterol for membrane function and growth, using UGA codon for tryptophan, passing through "bacterial-retaining" filters, and displaying genetic economy that requires a strict dependence on the host for nutrients and refuge. In addition, many of the mycoplasmas pathogenic for humans and animals possess extraordinary specialized tip organelles that mediate their intimate interaction with eucaryotic cells. This host-adapted survival is achieved through surface parasitism of target cells, acquisition of essential biosynthetic precursors, and in some cases, subsequent entry and survival intracellularly. Misconceptions concerning the role of mycoplasmas in disease pathogenesis can be directly attributed to their biological subtleties and to fundamental deficits in understanding their virulence capabilities. In this review, we highlight the biology and pathogenesis of these procaryotes and provide new evidence that may lead to increased appreciation of their role as human pathogens.