Using family systems theory as a theoretical framework, we investigated direct and indirect associations between type of disability, caregiver burden, and sibling relationships with structural equation modeling. We recruited 172 families raising typically developing children or a child with a disability. Participants volunteered at meetings and workshops for families of children with disabilities and were also recruited through snowball sampling. Mothers and fathers independently completed self-report questionnaires on caregiver burden and perceptions of the sibling relationship. Mothers experienced higher levels of caregiver burden than fathers. Parents of children with autism reported higher levels of caregiver burden than parents of typically developing children. Mothers of children with Down syndrome and multiple disabilities reported more positive sibling relationships than mothers of typically developing children. Mothers’ and fathers’ perceptions of caregiver burden were negatively related to their perceptions of the sibling relationship. Caregiver burden mediated the relationship between having a child with autism and positive sibling relationships. Results indicate the benefits of using a systems framework in examining families raising children with disabilities. Future research should focus on interventions for families of children with disabilities that help alleviate parental burden and foster positive sibling relationships.