Immunohistochemical detection of p21-ras to identify and characterize preneoplastic or neoplastic lesions in human tissues is reviewed. Information concerning the commercially available antibodies is presented. Antibodies DWP, Ras-10, Y13-259, YA6-172, NCC-001, and NCC-004 are fully documented with respect to their behavior in appropriate specificity tests and appear to be reliable reagents. After reviewing the data we have identified three groups of tissues or organs with respect to positive immunostaining for p21-ras as the significant criterion of malignancy. These three groups comprise (1) tissues for which no definite conclusion could be drawn (colon, lung, bladder, ovary, and neural and odontogenic tissues) despite occasional claims to the contrary, (2) tissues for which conclusions were negative (pancreas and stomach), and (3) tissues for which p21-ras staining positively discriminated malignant from normal tissues (liver, uterus, and salivary gland). Immunohistochemically detectable levels of products from a mutated ras gene could be demonstrated in a fraction of the samples from colon, lung, and bladder carcinomas, as well as in some histologically normal tissues adjacent to a colon carcinoma. The possibility that a higher relative intensity of the immunostaining reaction for p21-ras might discriminate malignant tissues from normal tissues or benign lesions in breast, pancreas, stomach, lung, uterus, or thyroid samples is suggested. Further studies now appear warranted and a strategy is proposed to validate the conclusions reached thus far.