We examined the effects of 3 diets differing in their relative levels of sugar and protein on development and metabolic pools (protein, TG, and glycogen) among sets of isofemale lines of 2 ecologically distinct Drosophila species, D. melanogaster and D. mojavensis. Our high protein:sugar ratio diet contained 7.1% protein and 17.9% carbohydrate, the EPS diet was 4.3% protein and 21.2% carbohydrate, and the LPS was only 2.5% protein and 24.6% carbohydrate. Larvae of D. melanogaster, a generalist fruit breeder, were able to survive on all 3 diets, although all 3 metabolic pools responded with significant diet and diet × line interactions. Development was delayed by the diet with the most sugar relative to protein. The other species, D. mojavensis, a cactus breeder ecologically unaccustomed to encountering simple sugars, completely failed to survive when fed the diet with the highest sugar and showed very poor survival even with the diet with equal parts of protein and sugar. Furthermore, the D. mojavensis adult metabolic pools of protein, TG, and glycogen significantly differed from those of D. melanogaster adults fed the identical diet. Thus, considerable within- and between-species differences exist in how diets are metabolized. Given that the genomes of both of these Drosophila species have been sequenced, these differences and their genetic underpinnings hold promise for understanding human responses to nutrition and for developing strategies for dealing with metabolic disease.