Our understanding of development and prevention of venous thromboembolism (VTE) has improved dramatically since Virchow described the triad of stasis, hypercoagulability, and endothelial dysfunction during the mid-1800s. A full arsenal of effective pharmacological and mechanical methods can help prevent VTE and many professional organizations have provided extensive evidence-based statements for VTE prophylaxis. Disappointingly, however, VTE has remained the major preventable cause of hospital death. Adherence rate to clinical guidelines is undesirably low. Many real-world patients have also been excluded from VTE prevention trials and hence practice guidelines recommendations. The comprehensive and repetitious formats of many available guidelines also limit their readability and applicability by nonthrombosis specialists. Moreover, some patients suffer from VTE despite complying with the contemporary prophylaxis regimens. Besides, significant heterogeneity exists in thromboprophylaxis practice and pitfalls between different countries. Last but not the least; although many at-risk patients are underprophylaxed, there is evidence to suggest that overprophylaxis (i.e., prescription of thromboprophylaxis in low-risk patients) comprises another important problem. We review the thromboprophylaxis practice and pitfalls around the world and provide recommendations on how the major obstacles can be overcome.