Mercury (Hg) is a non-essential, naturally occurring metal with many industrial uses. Most forms of Hg are highly toxic to both prokaryotic and eukaryotic organisms. There are no known biological proteins or processes that require Hg; however, unlike most non-essential metals, several protein-based processes have evolved to aid in Hg detoxification. This chapter outlines and discusses the mechanisms by which Hg enters and is handled by cells. In particular, similarities and differences between the effects of elemental and ionic Hg are highlighted in both prokaryotic and eukaryotic cells. The processes involved include Hg resistance, transport mechanisms, cellular distribution, and detoxification.