Cell culture systems that respond to the combined action of initiating chemical carcinogens, tumor promoters, and transforming viruses represent useful model systems for studying the complex multifactor nature of the carcinogenic process. We have utilized both secondary rat embryo (2 degrees RE) and a clonal population of established Fischer rat embryo (CREF) cells to study the effect of multiple agents on the process of adenovirus transformation. In the present review we summarize our investigations on the effects of polycyclic aromatic hydrocarbons, tumor promoters, a bee venom polypeptide-melittin (MEL), and the polypeptide hormone epidermal growth factor (EGF) on transformation of rat embryo cells by a temperature-sensitive mutant of human adenovirus type 5 (H5ts125). We also describe the effect of tumor promoters on the progression of the transformed phenotype, ie the temporal acquisition of anchorage-independent growth in adenovirus-transformed clones and the ability of MEL and EGF to elicit effects similar to those of tumor promoters in adenovirus-transformed cells.