Human tissue cell lines from each of the three primary germinal sources, ectoderm (conjunctiva and carcinoma of the buccal mucosa), entoderm (intestine and liver), and mesoderm (heart and monocytes) were inoculated with group A Streptococcus pyogenes, Staphylococcus aureus, and group D streptococci and were then observed. In addition, the effect of these bacteria on mouse fibroblasts was studied. All of the cell lines appeared to be equally susceptible to damage, but damage to the cells by S. pyogenes occurred only when living, actively multiplying bacteria were in contact with the tissue cells. Streptococcal products in the form of "used" growth medium had no observable effect on the cells. Cytopathogenic effects were first noticed about the time one would expect the bacteria to have reached the end of the log phase of growth. No damage to the tissue cells was noted when group A streptococci were separated from the cells by membrane filter diffusion chambers or dialyzing membranes, but a membrane did not protect cells from deleterious effects of staphylococci or group D streptococci. Group A streptococci survived in the tissue culture medium, but multiplication did not occur unless living tissue cells were present.