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Enteroviruses (EVs) include many human pathogens of increasing public health concern. These EVs are often associated with mild clinical manifestations, but they can lead to serious complications such as encephalitis, meningitis, pneumonia, myocarditis, or poliomyelitis. Despite significant advances, there is no approved antiviral therapy for the treatment of enterovirus infections. Due to the high genotypic diversity of EVs, molecules targeting highly conserved viral proteins may be considered for developing a “pan-EV” treatment. In this regard, the ATPase/Helicase 2C, which is a highly conserved non-structural protein among EVs, has essential functions for viral replication and is therefore an attractive antiviral target. Recent functional and structural studies on the 2C protein have led to the identification of molecules showing ex vivo anti-EV activity that is associated with resistance mutations on the coding sequence of the 2C protein. This review presents what is currently known about the 2C protein from an antiviral target perspective and discusses the way in which specific inhibitors work for this therapeutic target.