In this brief study, the origin and spread of the alchemical process of refining mercury in Tibetan medicine will be explored. Beginning with early sources from the eighth to the twelfth centuries, it will be argued that Orgyenpa Rinchenpel (O rgyan pa Rin chen dpal) caused a turning-point in the processing of mercury in Tibet by introducing a complex alchemical process previously unknown. This knowledge, including the manufacturing of new pills containing mercury, soon spread through Tibet and was incorporated into the medical expertise of local schools such as the Drangti school (Brang ti). Later it was most prominently practised by Nyamnyi Dorjé (Mnyam nyid rdo rje) in southern Tibet. This particular tradition was upheld by Chökyi Drakpa (Chos kyi grags pa) of the Drigung school, who taught it to his gifted student Könchok Dropen Wangpo (Dkon mchog 'gro phan dbang po). During the seventeenth century, two main transmission lines for refining mercury emerged, one associated with the Gelukpa school (Dge lugs pa) in Central Tibet and one with the Kagyüpa school (Bka' brgyud pa) and the Rimé movement (Ris med) in eastern Tibet. Both will be discussed in detail, highlighting important proponents and major events in their development. Finally, the situation in the twentieth century will be briefly explained.