The genetic factors that contribute to efficient food conversion are largely unknown. Several physiological systems are likely to be important, including basal metabolic rate, the generation of ATP, the regulation of growth and development, and the homeostatic control of body mass. Using whole-genome association, we found that DNA variants in or near proteins contributing to the background use of energy of the cell were 10 times as common as those affecting appetite and body-mass homeostasis. In addition, there was a genic contribution from the extracellular matrix and tissue structure, suggesting a trade-off between efficiency and tissue construction. Nevertheless, the largest group consisted of those involved in gene regulation or control of the phenotype. We found that the distribution of micro-RNA motifs was significantly different for the genetic variants associated with residual feed intake than for the genetic variants in total, although the distribution of promoter sequence motifs was not different. This suggests that certain subsets of micro-RNA are more important for the regulation of this trait. Successful validation depended on the sign of the allelic association in different populations rather than on the strength of the initial association or its size of effect.