Essential genes (EGs) play central roles in fundamental cellular processes and are required for the survival of an organism. EGs are enriched for human disease genes and are under strong purifying selection. This intolerance to deleterious mutations, commonly observed haploinsufficiency and the importance of EGs in pre- and postnatal development suggests a possible cumulative effect of deleterious variants in EGs on complex neurodevelopmental disorders. Autism spectrum disorder (ASD) is a heterogeneous, highly heritable neurodevelopmental syndrome characterized by impaired social interaction, communication and repetitive behavior. More and more genetic evidence points to a polygenic model of ASD and it is estimated that hundreds of genes contribute to ASD. The central question addressed in this dissertation is whether genes with a strong effect on survival and fitness (i.e. EGs) play a specific role in ASD risk. I compiled a comprehensive catalog of 3,915 mammalian EGs by combining human orthologs of lethal genes in knockout mice and genes responsible for cell-based essentiality. With an updated set of EGs, I characterized the genetic and functional properties of EGs and demonstrated the association between EGs and human diseases. Next I provided evidence for a stronger contribution of EGs to ASD risk, compared to non-essential genes (NEGs). By examining the exonic de novo and inherited variants from 1,781 ASD quartet families, I demonstrated a significantly higher burden of damaging mutations in EGs in ASD probands compared to their non-ASD siblings. Analysis of EGs in the developing brain identified clusters of co-expressed EGs implicated in ASD, among which I proposed a priority list of 29 EGs with potential ASD risk as targets for future functional and behavioral studies. Finally, I developed the essentiality burden score (EBS), which captures the burden of rare mutations in EGs as a novel polygenic predictor of individual ASD risk and a useful addition to the current tools for understanding the polygenic architecture of ASD. Overall, I show that large-scale studies of gene function in model organisms and human cell lines provide a powerful approach for prioritization of genes and pathogenic variants identified by sequencing studies of complex human disease.