Rivaroxaban is a Direct Oral Anticoagulant (DOAC), which has six licensed indications, including the use for prevention of stroke and systemic embolism with non-valvular Atrial Fibrillation (AF) and the treatment of Venous Thromboembolism (VTE). The pharmacokinetics and the pharmacogenetics of rivaroxaban are reviewed by the author because of a previously reported case of a 43-year-old Caucasian female, who was diagnosed with popliteal and calf Deep Venous Thrombosis (DVT) while on anticoagulation treatment in the form of rivaroxaban 20 mg PO daily. This treatment was started because of a previously verified bilateral Pulmonary Embolism (PE) 5 months earlier. Rivaroxaban is more frequently used in clinical practice, and many physicians are aware that rivaroxaban requires adaptation mainly on the patient's renal function. However, there is still a need to increase awareness of rivaroxaban's interactions with drugs that share its pathways when the hepatic CYP450 and/or P-gp/BCRP are involved. These pathways are utilized by several medications, which are used in cardiovascular and neurological diseases, and the treatment of infections. These interactions can result in under or overexposure to rivaroxaban, which both effects can be detrimental. The author makes several cautious suggestions to decrease the incidence of under/overexposure of rivaroxaban. Physicians, including primary care physicians, could receive a clinical course focusing on DOACs for anticoagulation treatment or direct clinical training within a short-term Anticoagulation Team (ACT) stewardship program concerning adequate prescriptions of rivaroxaban/DOAC as well as their interactions. Also, patients who are elderly and/or with polypharmacy while taking rivaroxaban require more frequent controls. Furthermore, research exploring the effects of ABCG1, ABCG2, CYP3A4, CYP3A5, and Drug-Drug Interactions (DDI), is warranted. Finally, there is a need to identify a validated method for measuring rivaroxaban in primary care.