Protein S (PS) is an extensively studied protein with an important function in the down‐regulation of thrombin generation. Because of the presence of a pseudogene and two different forms of PS in plasma, a bound and a free form, it is one of the most difficult thrombophilias to study. A deficiency of PS predisposes subjects to (recurrent) venous thromboembolism (VTE) and foetal loss. However, the conundrum of diagnosing PS deficiency has led to conflicting reports of PS as a risk factor for VTE. In this review, we aim to present a clinical perspective of PS deficiency.