SIGNIFICANCE: The dual-specificity phosphatases (DUSPs) constitute a 
heterogeneous group of cysteine-based protein tyrosine phosphatases, whose 
members exert a pivotal role in cell physiology by dephosphorylation of 
phosphoserine, phosphothreonine, and phosphotyrosine residues from proteins, as 
well as other non-proteinaceous substrates.
RECENT ADVANCES: A picture is emerging in which a selected group of DUSP enzymes 
display overexpression or hyperactivity that is associated with human disease, 
especially human cancer, making feasible targeted therapy approaches based on 
their inhibition. A panoply of molecular and functional studies on DUSPs have 
been performed in the previous years, and drug-discovery efforts are ongoing to 
develop specific and efficient DUSP enzyme inhibitors. This review summarizes 
the current status on inhibitory compounds targeting DUSPs that belong to the 
MAP kinase phosphatases-, small-sized atypical-, and phosphatases of 
regenerating liver subfamilies, whose inhibition could be beneficial for the 
prevention or mitigation of human disease.
CRITICAL ISSUES: Achieving specificity, potency, and bioavailability are the 
major challenges in the discovery of DUSP inhibitors for the clinics. Clinical 
validation of compounds or alternative inhibitory strategies of DUSP inhibition 
has yet to come.
FUTURE DIRECTIONS: Further work is required to understand the dual role of many 
DUSPs in human cancer, their function-structure properties, and to identify 
their physiologic substrates. This will help in the implementation of therapies 
based on DUSPs inhibition.