BACKGROUND Selenoprotein synthesis requires the reinterpretation of a UGA stop codon as one that encodes selenocysteine (Sec), a process that requires a set of dedicated translation factors. Among the mammalian selenoproteins, Selenoprotein P (SELENOP) is unique as it contains a selenocysteine-rich domain that requires multiple Sec incorporation events. METHODS In this review we elaborate on new data and current models that provide insight into how SELENOP is made. CONCLUSIONS SELENOP synthesis requires a specific set of factors and conditions. CONCLUSIONS As the key protein required for proper selenium distribution, SELENOP stands out as a lynchpin selenoprotein that is essential for male fertility, proper neurologic function and selenium metabolism.