The devastating consequences of venous thromboembolism have forever provided the impetus to explore safe and effective treatment strategies. To date, the pathophysiology and mechanism of thrombosis have been extensively studied and details of new thrombophilic conditions are continually being discovered. Although there has been extensive research detailing various predispositions to thrombosis, uncertainties regarding their appropriate management continue. This review aims to highlight the various challenges involved in identifying those at risk; provide appropriate management options; and lastly present the current views on the development of new anticoagulants that are competing to replace the traditional agents.