The R3230AC rat mammary adenocarcinoma is a transplantable tumor model, which can be subcultured in vitro and does not metastasize spontaneously. However, when cell suspensions of this tumor are injected intravenously, multiple lung foci develop. These foci were used as source for a cell subpopulation. Prolonged exposure of the original tumor cell line to increasing levels of lectins (concanavalin A and wheat germ agglutinin) resulted in the development of a lectin-resistant subpopulation. Through experimental in vitro exposure to the antiestrogenic compound tamoxifen citrate, a tolerant, karyotypically defined subpopulation was obtained. In the four cell lines studied, heterogeneity was observed in the following parameters: doubling time, steroid receptors, and median chromosome counts. Statistically discernible differences were found. This may represent a model for the effect of selective pressures in the tumor environment, such as endocrine manipulation, leading to the gradual development of resistant cell lines and treatment failure.