Most genetic research has used inbred organisms and has not explored the complexity of natural genetic variation present in outbred populations. The translation of genotype to phenotype is complicated by gene interactions observed as epistasis, canalization, robustness, or buffering. Analysis of double mutations in inbred experimental organisms suggests some principles for gene interaction that may apply to natural variation as well. The buffering of variation in one gene is most often due to a small number of other genes that function in the same biochemical process. However, buffering can also result from genes functioning in processes extrinsic to that of the primary gene.