The review by Werling and Geschwind explores the sex differences in autism spectrum disorder (ASD) prevalence and phenotypic presentation, aiming to understand the biological basis for the male bias in ASD. Recent studies consistently report a male bias in ASD prevalence, but also suggest that females may present with fewer restricted and repetitive behaviors and externalizing behavioral problems. Genetic studies indicate that females are protected from the effects of heritable and *de novo* ASD risk variants, and sex chromosomal genes and sex hormones, particularly testosterone, may modulate the effects of genetic variation on the autistic phenotype. The review discusses the multifactorial liability models for ASD, including the multiple-threshold model and the total liability model, and highlights the importance of sex-specific biology in understanding the mechanisms behind the male bias in ASD. Future research is needed to elucidate the precise cellular and molecular mechanisms by which sex-differential factors interact with genetic and environmental risk factors to influence ASD risk.The review by Werling and Geschwind explores the sex differences in autism spectrum disorder (ASD) prevalence and phenotypic presentation, aiming to understand the biological basis for the male bias in ASD. Recent studies consistently report a male bias in ASD prevalence, but also suggest that females may present with fewer restricted and repetitive behaviors and externalizing behavioral problems. Genetic studies indicate that females are protected from the effects of heritable and *de novo* ASD risk variants, and sex chromosomal genes and sex hormones, particularly testosterone, may modulate the effects of genetic variation on the autistic phenotype. The review discusses the multifactorial liability models for ASD, including the multiple-threshold model and the total liability model, and highlights the importance of sex-specific biology in understanding the mechanisms behind the male bias in ASD. Future research is needed to elucidate the precise cellular and molecular mechanisms by which sex-differential factors interact with genetic and environmental risk factors to influence ASD risk.