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Systemic lupus erythematosus (SLE) results from complex abnormalities of the innate and acquired immune systems. For reasons that are currently not well understood, the disease course and phenotype associated with SLE, although quite variable, are generally more severe when the diagnosis is made during childhood. Active disease, infections, lupus nephritis, and neuropsychiatric SLE manifestations are associated with higher morbidity and mortality. Unlike in adult-onset SLE, systemic glucocorticoid therapy and immunosuppressive medications are needed for the treatment of the majority of children and adolescents with SLE. The complex nature of childhood-onset SLE demands a comprehensive, multidisciplinary management approach that considers the patients' growth and development, their educational needs, and the unpredictable course of SLE and its complications.