Recurrent pregnancy loss (RPL) is a devastating reproductive problem affecting approximately 5% of couples trying to conceive. Genetic factors appear to be highly associated with reproductive loss. In this article, genetic factors are reviewed in terms of random numerical chromosome errors in miscarriage specimens and carriers of structural chromosome rearrangements that may result in unbalanced chromosome errors in pregnancies. Recently, research has generated interest in genetic markers for recurrent loss such as skewed X-chromosome inactivation and human leukocyte antigen-G polymorphisms. Assisted reproductive technologies (specifically, preimplantation genetic diagnosis) have been offered to couples with recurrent pregnancy loss; however, more data need to be evaluated before routine use can be advocated. Management of genetic factors in RPL should include therapy based on the highest level of evidence, genetic counseling, and close monitoring of subsequent pregnancies.