We present a patient with chronic insomnia resistant to traditional pharmacologic (e.g., sedative-hypnotics) and nonpharmacologic (e.g. cognitive behavioral therapy for insomnia; CBT-I) therapy. A finding of elevated serum homocysteine triggered a whole genome sequencing analysis which revealed a homozygous methylenetetrahydrofolate reductase (MTHFR) gene polymorphism (C677T/C677T; dbSNP rs1801133). Interventions targeting her polymorphism-dependent loss of function successfully resolved her insomnia. This case demonstrates a genomic approach for insomnia whereby successful treatment was focused on optimizing the patient’s metabolome which was altered as a result of a missense single nucleotide polymorphism.