For more than 40 years microbiologists have known that bacteria with absent or defective cell walls could survive and even multiply. Such pleomorphic or spherical variants of bacteria have been commonly called protoplasts, spheroplasts, and L-forms. Although these terms have been used interchangeably, a more precise definition of each, based on the amounts of cell wall remaining and ability to reproduce, has been recently recommended. Cell-wall-defective bacterial variants can be produced in the laboratory by antibiotics such as penicillin or other agents which damage or inhibit the synthesis of the bacterial cell wall. Variants do not usually multiply on routine bacteriologic media but may reproduce if osmotically stabilized in hypertonic media enriched with serum. By use of such special media, wall-defective bacteria and fungi have been isolated from all types of clinical specimens (blood, spinal fluid, urine, pus, and tissues such as kidney and lymph node). The role which wall-defective variants play in human disease is not yet well defined. Animal studies suggest they are rarely pathogenic as a result of invasion and multiplication. However they can produce toxins and immunogens and can persist silently in a host, particularly one being treated with penicillin or related antibiotics, and later revert to the virulent parent. Thus it is possible that wall-defective variants produce disease via toxic or immune mechanisms or serve as persister forms of microorganisms in chronic and relapsing infections. Antibiotics directed against the metabolism of the cell or cell membrane of the etiologic agent, rather than against the synthesis of the cell wall, may sometimes control such infections.