PURPOSE OF REVIEW: Biologics and novel targeted therapeutics have transformed the management of pediatric rheumatic diseases over the past two decades; however, questions about short-term and long-term safety remain. Safety data gathered from recent clinical trials, long-term extensions of prior trials, registries, and other real-world evidence are summarized here for biologics and novel therapeutics commonly prescribed for pediatric rheumatic diseases. RECENT FINDINGS: With nearly 20 years of therapeutic experience, tumor necrosis inhibitors (TNFi) are generally well tolerated, although infections, malignancy, and development of new autoimmunity remain a concern. Risk of infections may be higher in IL-1 and IL-6 inhibitors, and lower in abatacept, compared with TNFi. Safety data for B-cell-targeted therapeutics and janus kinase inhibitors are emerging, but remain limited, especially in children. SUMMARY: Biologic and novel targeted therapeutics offer a promising future for children with pediatric rheumatic disease. However, long-term safety data in children remain limited for several agents. With any therapeutic option, both short-term and long-term safety concerns must be weighed against individual clinical needs when choosing the optimal treatment for each child.