Normal development and function of metazoan organisms depend on oxygen availability. The level of oxygen can be sensed by individual cells, which respond to reduced oxygenation (hypoxia) largely through activation of hypoxia-inducible factor-1 (HIF-1). At the organism level the response to hypoxia involves an increase in red blood cell production. Within tissues, HIF activation increases the blood supply and blood vessel growth. At the individual cell level it is manifested as an increase in anaerobic metabolism in order to sustain basic cellular functions. Iron is central to the oxygen sensing mechanism, and sensitivity to other metals, namely cobalt and nickel, is a distinctive feature of the HIF system; in fact, this is often used as an initial way of implicating HIF-1 in a biological response. Historically, the fact that nickel or cobalt mimicked hypoxia provided an important clue as to the nature of the oxygen sensing mechanism. It also raises the possibility that nickel or cobalt exposure may have important toxic and pathological effects mediated by HIF activation. Here we review the implications of the metal sensitivity of the HIF-1 system, and examine the hypothesis that HIF-1 activation may play an important role in metal induced carcinogenesis.