Although the pace of gene discovery for rare genetic diseases has accelerated during the past decade, in part, due to the success of the Human Genome Project, translation of these discoveries to clinical utility has lagged behind. In particular, identification of the gene responsible for a Mendelian disorder immediately presents the opportunity for molecular genetics diagnostics to confirm clinical diagnoses, provide accurate genetic counseling information and recurrence risks, as well as carrier testing and prenatal diagnosis opportunities for families. To move these discoveries from a research setting to clinical utility, we describe two successful models for partnerships between research laboratories with Clinical Laboratory Improvement Amendments-certified clinical molecular diagnostic laboratories. Contrary to common misconceptions, molecular genetic testing for very rare diseases can be performed in a high-quality clinical setting in a financially self-sustaining or even profitable manner. Key elements to the success of these models include a Clinical Laboratory Improvement Act-certified diagnostic laboratory with a commitment to very rare genetic disease testing, active involvement of genetic counselors and clinical geneticists, and partnerships with research experts and patient support groups specific to each disease.