Patients with cancer are at a high risk of symptomatic venous thromboembolism (VTE), which is a common cause of morbidity and mortality in this patient population. Increased risk of recurrent VTE and bleeding complications are two major challenges associated with therapeutic anticoagulation in these patients. Long-term therapy with low-molecular-weight heparins (LMWHs) has been the standard of care for the treatment of cancer-associated VTE given its favorable risk-benefit ratio in comparison with vitamin K antagonists. Direct oral anticoagulants (DOACs), which offer the convenience of oral administration and have a rapid onset of action, have recently emerged as a new treatment option for patients with cancer-associated thrombosis (CT). Randomized clinical trial data with head-to-head comparisons between DOACs and LMWHs showed that overall, DOACs have a similar efficacy profile but a higher risk of bleeding was observed in some of these studies. This review aims to identify unmet needs in the treatment of CT. We discuss important considerations for clinicians tailoring anticoagulation (1) drug-drug interactions, (2) risk of bleeding (e.g., gastrointestinal bleeding), (3) thrombocytopenia, hematological malignancies, (4) metastatic or primary brain tumors, and (5) renal impairment. Additional research is warranted in several clinical scenarios to help clinicians on the best therapeutic approach., Competing Interests: Conflicts of Interest Anna Falanga is a professor of Haematology at the University of Milano-Bicocca and Director of the Department of Immunohematology and Transfusion Medicine in Bergamo, Italy. She has received personal fees for participation in advisory boards and lectures from Instrumentation Laboratory, Stago, Bayer, Sanofi, ROVI Pharmaceuticals, and Leo Pharma. Grégoire Le Gal holds the Chair on Diagnosis of Venous Thromboembolism, Department of Medicine, University of Ottawa and has received a Mid-Career Clinician–Scientist Award from the Heart and Stroke Foundation of Canada. Marc Carrier has received funding for research from BMS, Pfizer, and Leo Pharma, and personal fees from Bayer, BMC, Pfizer, Sanofi, Servier, and Leo Pharma. Hikmat Abdel-Razeq has nothing to report. Cihan Ay has received honoraria/personal fees for lectures from Bayer, Daiichi-Sankyo, and BMS/Pfizer and participated in the advisory boards for Bayer, Sanofi, Daiichi Sankyo, and BMS/Pfizer. Andrés J. Muñoz Martin is Head of Cancer & Thrombosis Section of the Spanish Society of Medical Oncology (SEOM) and coordinator of the TESEO-SEOM registry of cancer-associated thrombosis. He has provided consultation and lectures and participated in advisory boards of Sanofi, Celgene, AstraZeneca, Roche, Leo Pharma, Servier, Pfizer, Bristol-Myers Squibb, Daiichi Sankyo, Bayer, Amgen, Rovi, Merck Sharp & Dohme, and Eli Lilly. He has also received funding for research from Sanofi, Leo Pharma, and Celgene. Travel and accommodations expenses have been borne by Roche, Merck Serono, Amgen, and Celgene. Inventor with Dr. José Manuel Soria: Genetic Risk Score in VTE and Cancer. Ana Thereza Rocha received personal fees for participation in advisory boards and for lectures from Bayer, Daiichi/Sankyo, Boehringer Ingelheim and Sanofi Giancarlo Agnelli reports personal fees from Bristol Myers Squibb, Pfizer, Bayer Healthcare, and Daiichi Sankyo outside the submitted work Ismail Elalamy has provided lectures and participated in advisory boards of Aspen, Sanofi, Bayer, Bristol-Myers Squibb, Pfizer, Leo Pharma, Rovi, and Boehringer Ingelheim. Benjamin Brenner has received honorarium for participation in advisory boards and lectures from Bayer, Sanofi, Rovi Pharmaceuticals, and Leo Pharma., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)