Tumor necrosis factor (TNF)-targeted therapies are increasingly being prescribed in the management of a variety of inflammatory and autoimmune diseases. The use of this class of medications also pose risks of developing an assortment of pulmonary side effects including infections (TB, bacterial, and fungal infections), pulmonary nodules, chronic pneumonitis/fibrosis, SLE-like reactions, vasculitis, and exacerbations of underlying lung disease. In addition to surveillance for tuberculosis prior to initiation of TNF-targeted therapy, a high level of vigilance should be maintained during administration for infectious and non-infectious complications, even years into a patient’s course. The available evidence argues for caution in using these agents in patients with pre-existing lung disease and heightened suspicion of accelerated nodule formation in those with preexisting rheumatoid nodules. Management centers on excluding infection, identifying confounders (especially methotrexate or pre-existing lung disease), and promptly discontinuing TNF-targeted therapy. In some instances, invasive procedures (e.g. bronchoscopy or VATS lung biopsy) will be necessary to establish the proper diagnosis, and the administration of steroids may be beneficial.