The data reviewed here demonstrate that there are many similarities in growth and cellular characteristics for different types of tumor cells grown as multicell spheroids. Furthermore, where comparisons have been made many of the features of spheroids also occur in tumors in vivo. However, as for tumors, there are also many characteristics of individual types of spheroids which are relatively specific and cannot be generalized as properties of all spheroid model systems. The results also demonstrate the marked influence which cellular microenvironments regulated by a supply of oxygen and nutrients may have on the development of cellular heterogeneity. Furthermore, using spheroids it was shown that dynamic cellular and metabolic interactions exist in regulating the development of cellular subpopulations and microenvironments. Spheroids are more sensitive to alterations in culture environment than are monolayer or single-cell suspension cultures. Consequently, researchers who use this model system must characterize, optimize, and standardize the growth conditions for the spheroid cell type being investigated. This information then provides a base from which to undertake detailed studies, which are not possible in experimental tumors, of controlled manipulation of microenvironments in spheroids. The ranges of cellular microenvironments and cellular heterogeneity which exist at different stages of spheroid growth provide a model, at least in part, for coexisting size ranges of microregions in many solid tumors. Thus, spheroids provide a model, which at different stages of growth is readily manipulated and controlled experimentally, to facilitate studies of contributions of individual environmental factors, or concomitant changes in these, on cellular phenotypic expression. It is probable that the cellular changes which can be demonstrated to occur during spheroid growth, also occur in vivo. Modulation of cellular characteristics revealed by research with spheroids requires much more study to determine the mechanisms and effects on tumor cell behavior, as well as response to therapeutic agents and their relevance to tumors in vivo.