Since 1999, human parechoviruses (HPeVs) have been classified as a separate group in the large and expanding family of Picornaviridae. In contrast to the well-established group of the human enteroviruses (HEVs), HPeVs have long been considered as irrelevant and have only been associated with mild disease manifestations in children. The identification of HPeV-3 in 2004 and its association with neonatal sepsis, refocused attention on this neglected group of viruses. Clinically HPeV infections may mimic HEV infections and are increasingly recognized as viral causes of sepsis-like illness and CNS infections in young children. Therapy is not available against HPeVs or HEVs. In this article, we will demonstrate that therapy against this group of picornaviruses is urgently needed and we will review the current knowledge of treatment options as well as the current developments in antiviral therapy against picornaviruses in the scope of treatment possibilities against HPeVs.