PURPOSE OF REVIEW: A single genetic diagnosis, especially from the analysis of a limited number of genes, may not signal the end of a diagnostic odyssey. When a patient with a genetic syndrome presents with symptoms that are not usually associated with their disease phenotype, additional genetic testing is warranted. RECENT FINDINGS: Although multiple co-existing genetic diagnoses may sound unlikely, many recent studies and case reports have demonstrated that this scenario is more common than expected. Studies involving whole exome and genome sequencing have identified a frequency of multiple genetic diagnoses and have identified clinical findings that make a second diagnosis more likely, which we have seen reflected in recent cases from our own clinic and consult service. These include multisystem disease, consanguinity, well described aneuploidies with rare or new symptoms, and complex structural chromosomal anomalies which may include multiple chromosomes and breakpoints that disrupt gene function. SUMMARY: Identifying a second diagnosis can have vast implications for patient management and counseling. Patients can be followed with appropriate medical screening and early interventions to support optimal child development. Furthermore, the patient's family can be impacted by ending the diagnostic odyssey, providing testing for other at-risk family members, and offering prenatal options.