Fibrosis, inflammation and vascular dysfunction are major features of systemic sclerosis and the multiple organ-specific complications that characterize this disease. Several manifestations of systemic sclerosis, including Raynaud's phenomenon, digital ulceration, scleroderma renal crisis and pulmonary arterial hypertension, contribute significantly to morbidity and mortality and are understood to share similarities in their underlying vasculopathy. In recent years, a number of treatment options have become available that ease the burden of these manifestations, including calcium channel blockers, angiotensin converting enzyme inhibitors, prostanoids and prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase type-5 inhibitors. Several of these treatments have demonstrated beneficial effects against more than one complication, as a result of the similarities in the pathology underlying these manifestations. However, physicians involved in the management of patients with systemic sclerosis are faced with differing levels of evidence supporting these treatments, and historically little international consensus on the treatment of some manifestations, such as digital ulcers. The aim of this article is to evaluate the level of evidence supporting each intervention in systemic sclerosis, thereby facilitating decision-making in the clinic.