Schools provide important services that cannot be provided virtually to children with medical complexity and children with intellectual and developmental disabilities, yet these children are among the most at risk from coronavirus disease 2019 (COVID-19). To keep schools open for children with medical complexity and/or intellectual and developmental disabilities during the COVID-19 pandemic, we implemented severe acute respiratory syndrome coronavirus 2 testing at 3 sites across the United States. We evaluated testing strategies for staff and students at each site, including specimen source (nasopharyngeal or saliva), test type (polymerase chain reaction or rapid antigen), and frequency and type (screening versus exposure/symptomatic) of testing provided. Among the greatest barriers to severe acute respiratory syndrome coronavirus 2 testing in these schools was the engagement of caregivers and challenges navigating legal guardianship for consenting adult students. Additionally, variability in testing strategies nationally and in the community, as well as surges in viral transmission across the United States during the course of the pandemic, led to testing hesitancy and variable participation rates. Essential to the successful implementation of testing programs is building a trusted relationship with school administrators and guardians. Leveraging our experiences with COVID-19 and forming lasting school partnerships can help keep schools for vulnerable children safe in future pandemics.