This chapter focuses on evidence for increased nuclear genome instability in autism. Duplication and deletions of specific chromosome segments leading to altered gene dosage (copy number variants CNVs) are common in autism. Additional evidence for genomic instability is the higher frequency of nucleotide mutation in nuclear DNA in autistic probands relative to siblings or controls. At least 300 different regions in the nuclear genome are sites of autism-associated copy number variants. Specific cases of autism differ in the number and position of copy number variants and mutations indicating substantial genetic heterogeneity. There are however at least eight different chromosome regions that are sites of recurrent rare copy number variants in autistic probands. Specific genes impacted by copy number variants and dosage changes in some individuals may be impacted by mutations in other cases. Genes impacted by copy number variants and/or mutations in autistic probands often encode products that are important to neuronal synaptic structure and function. Mitochondrial function is impaired in some autism cases. This may be due to alterations in one or more of the 2,000 nuclear genes that encode enzymes and proteins that function within mitochondria. Mitochondrial DNA mutations are apparently not common in autism. Epigenetic processes including chromatin methylation impact gene expression. Hypomethylation of DNA leads to genomic instability. Metabolic processes involved in the generation of methyl donors for methylation and processes involved in homeostasis of oxidation and reduction balance are impacted in some autism cases; both pathways can be disrupted by environmental factors.