Venous thromboembolism (VTE) is a common complication in ambulatory cancer patients receiving chemotherapy. Current clinical guidelines recommend against the use of routine primary thromboprophylaxis in unselected ambulatory cancer patients. The Khorana score is a risk assessment tool derived and prospectively validated for the identification of cancer patients at high risk of thrombotic complications. Recently, 2 randomized, controlled trials have assessed the use of low-dose direct oral Xa inhibitors, apixaban and rivaroxaban, for the prevention of cancer-associated thrombosis in ambulatory patients at intermediate to high risk of VTE (Khorana score ≥2). Taken together, these trials have shown that low-dose direct oral Xa inhibitors reduce the risk of VTE in this patient population without a significant increase in major bleeding. These results should encourage clinicians to consider the use of primary thromboprophylaxis in ambulatory cancer patients at intermediate to high risk of VTE who do not have any apparent risk factors for bleeding. The direct oral Xa inhibitors have also been assessed in the acute management of cancer-associated thrombosis. Current evidence suggests that these drugs are a convenient, effective, and safe option for the management of acute VTE in many cancer patients. Low-molecular weight heparin, however, may continue to be the treatment of choice depending on the presence of bleeding risk factors, the type of cancer, drug-drug interactions, and patient preferences.