Current evidence-based clinical practice guidelines recommend the use of both low-molecular-weight heparin (LMWH) and direct factor Xa inhibitors (apixapan, edoxaban and rivaroxaban) as first-line options for the treatment of venous thromboembolism (VTE) in patients with cancer. However, most of these guidelines refer to the general cancer patient population and provide limited guidance for specific subgroups of patients at particularly high risk of bleeding, such as those with gastrointestinal cancers, primary or metastatic brain tumors, thrombocytopenia, or renal impairment. In these complex populations, the management of cancer-associated thrombosis (CAT) poses unique challenges and requires a nuanced approach based on the primum non nocere principle. This comprehensive review critically examines the relevant literature and discusses the therapeutic options currently available for the management of CAT in these special situations.