DUSP5 and DUSP6/MKP-3 are members of a structurally distinct subfamily of ten dual-specificity (Tyr/Thr) protein phosphatases, which are responsible for the regulated dephosphorylation and inactivation of mitogen-activated protein kinases (MAPKs) in mammalian cells and tissues. DUSP6/MKP-3 is a cytoplasmic phosphatase, which acts in a negative feedback loop to regulate the activity of the classical ERK1 and ERK2 MAPKs. DUSP5 is also a specific ERK phosphatase. However, it is a nuclear enzyme and may also act as a nuclear anchor for ERK1 and ERK2. Despite our knowledge of their biochemical activities in terms of MAPK substrate specificity and catalytic mechanism, much less is known about the regulation and physiological functions of DUSP5 and DUSP6. In particular, it is unclear if these phosphatases play any role in the regulation of ERK signalling in response to activated oncogenes. We have generated mice with targeted deletions of the genes encoding DUSP5 and DUSP6 and are studying the effects of gene loss in both cultured cells and in mouse models of cancer. Our data thus far would indicate that these enzymes may be important regulators of oncogenic signalling and that loss of function can result in an increased frequency and more rapid progression of Ras-induced carcinogenesis.