Pulmonary veno-occlusive disease (PVOD) is an orphan disease and uncommon etiology of pulmonary arterial hypertension (PAH) characterized by substantial small pulmonary vein and capillary involvement. PVOD, also known as 'PAH with features of venous/capillary involvement' in the current ESC/ERS classification. In recent years, particular risk factors for PVOD have been recognized, including genetic susceptibilities and environmental factors (such as exposure to occupational organic solvents, chemotherapy, and potentially tobacco). The discovery of biallelic mutations in the EIF2AK4 gene as the cause of heritable PVOD has been a breakthrough in understanding the molecular basis of PVOD. Venous and capillary involvement (PVOD-like) has also been reported to be relatively common in connective tissue disease-associated PAH (especially systemic sclerosis), and in rare pulmonary diseases like sarcoidosis and pulmonary Langerhans cell granulomatosis. Although PVOD and pulmonary arterial hypertension (PAH) exhibit similarities, including severe precapillary PH, it is essential to differentiate between them since PVOD has a worse prognosis and requires specific management. Indeed, PVOD patients are characterized by poor response to PAH-approved drugs, which can lead to pulmonary edema and clinical deterioration. Due to the lack of effective treatments, early referral to a lung transplantation center is crucial.