We investigated dietary modulation, by energy level and energy source, of two-stage skin tumorigenesis initiated with 7,12-dimethylbenz(a)anthracene and promoted with 12-O-tetradecanoylphorbol-13-acetate in SENCAR mice. Studies comparing the influence of dietary calorie restriction (feeding less carbohydrate and less fat) with diet restriction and with ad libitum control feeding indicated an inhibition of papillomas and carcinomas in both restricted groups. The inhibition was greatest in the calorie-restricted group. We reported an increase in the number and incidence of papillomas and the earlier appearance of carcinomas in mice fed a high-fat diet during promotion, in comparison with control groups fed the same calorie allotment. Recent work compared restriction of fat calories (high carbohydrate, restricted fat) with restriction of carbohydrate calories (high fat, restricted carbohydrate), and both protocols resulted in fewer papillomas and carcinomas. Restriction of fat calories resulted in a greater inhibition of papillomas, whereas carcinoma rates were comparable with both protocols. Protein kinase C activity in epidermal cells from mice fed the high-fat diet was higher than activity from mice fed the control diet. Calorie restriction reduced protein kinase C activity. Phosphatidylinositol-inositol phosphate labeling studies suggest alteration of inositol lipid turnover in epidermal cells from mice fed a calorie-restricted diet.