Inborn errors of immunity are a heterogeneous group of monogenic immunologic disorders caused by mutations in genes with critical roles in the development, maintenance, or function of the immune system. The genetic basis is frequently a mutation in a gene with restricted expression and/or function in immune cells, leading to an immune disorder. Several classes of inborn errors of immunity, however, result from mutation in genes that are ubiquitously expressed. Despite the genes participating in cellular processes conserved between cell types, immune cells are disproportionally affected, leading to inborn errors of immunity. Mutations in DNA replication, DNA repair, or DNA damage response factors can result in monogenic human disease, some of which are classified as inborn errors of immunity. Genetic defects in the DNA repair machinery are a well-known cause of T⁻B⁻NK⁺ severe combined immunodeficiency. An emerging class of inborn errors of immunity is those caused by mutations in DNA replication factors. Considerable heterogeneity exists within the DNA replication–associated inborn errors of immunity, with diverse immunologic defects and clinical manifestations observed. These differences are suggestive for differential sensitivity of certain leukocyte subsets to deficiencies in specific DNA replication factors. Here, we provide an overview of DNA replication–associated inborn errors of immunity and discuss the emerging mechanistic insights that can explain the observed immunologic heterogeneity.