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Glucocorticoids (GCs) are widely used for inflammatory and autoimmune diseases. Their mechanism of action is most commonly rooted in genomic effects that have both beneficial and adverse consequences. The purpose of this review is to discuss the potential complications and side effects that may occur with GC use. Many of these complications are related to the dose and duration of therapy used. Evidence-based preventative strategies are discussed. Many recommendations are based on expert opinion and not on strong evidence. A 54-year-old man presents with proximal upper and lower extremity weakness. There are no rashes. The antinuclear antibody is negative; the erythrocyte sedimentation rate and C reactive protein are 24 mm/h and 3 mg/dL, respectively. An electromyography displays myopathic motor unit potentials with fibrillation and a muscle biopsy confirms polymyositis. Prednisone of 60 mg/d is initiated. What are the risks associated with GC use? What other studies and interventions should occur in this patient starting long-term GC therapy?