Females and males differ in physiology and in the incidence and progression of diseases. The sex-biased proximate factors causing sex differences in phenotype include direct effects of gonadal hormones and of genes represented unequally in the genome because of their X- or Y-linkage. Novel systems approaches have begun to assess the magnitude and character of sex differences in organization of gene networks on a genome-wide scale. These studies identify functionally related modules of genes that are coexpressed differently in males and females, and sites in the genome that regulate gene networks in a sex-specific manner. Measurement of the aggregate behavior of genes uncovers novel sex differences that can be related more effectively to susceptibility to disease.