Systemic capillary leak syndrome (SCLS) is due to increased capillary permeability to proteins and fluid extravasation from blood vessels into surrounding tissues and body cavities. This fluid extravasation leads to hypotension, generalized anasarca, pleural effusions, and pericardial effusions -- the more severe cases of SCLS can cause multiorgan dysfunction, including cardiovascular collapse, shock, and death. The treatment includes corticosteroids, diuretics, albumin, immunoglobulins, and crystalloids. SCLS is potentially fatal. Recognizing signs and symptoms early and treating the patients is essential as this condition is fatal. It sometimes is a diagnosis of exclusion, being very challenging to diagnose and treat. The lack of understanding of the underlying mechanisms causing SCLS and proper treatment guidelines, especially in cancer patients, made diagnosing and treating this condition hard. Reports show that many cancers and anti-cancer treatments, including newer immunotherapy, cause SCLS. The mortality rate of SCLS associated with cytotoxic chemotherapy is 24% at five years. This review focuses on the cancers and anti-cancer drugs causing SCLS, treating acute SCLS, and available preventive regimens. The fundamental purpose of this review is to help clinicians recognize SCLS early to avoid delays in diagnosis and treatment. We also would like to elaborate on the fact that research on cancer-related SCLS is critical for developing staging criteria, useful diagnostic markers, prevention, and treatment strategies for anti-cancer drug-induced SCLS to prevent early discontinuation of anti-cancer drugs.