Systemic sclerosis (SS) is characterized by sclerosis of the dermis and internal organs and by vascular abnormalities. Although the pathophysiology of the disease has been partly elucidated, the efficacy of long-term treatments remains limited, with no significant increase in survival in prospective studies. Conventional drug treatments are disappointing in clinical practice, and in a recent prospective randomized study standard-dose D-penicillamine was not more effective than mini-dose D-penicillamine. New long-term treatments are emerging for diffuse SS, including cyclophosphamide for patients with progressive interstitial lung disease or stem cell transplantation for those with early organ involvement. The most effective treatments remain symptomatic, such as angiotensin-converting enzyme inhibitors for acute renal crisis, calcium channel antagonists for Raynaud's phenomenon, and proton pump inhibitors for the complications of gastroesophageal reflux. This review article focuses on long-term treatments that are most likely to be effective and suggests symptomatic treatment strategies tailored to specific organ involvements.