The chikungunya virus (CHIKV) has become a substantial global health threat due to its massive reemergence, the considerable disease burden and the lack of vaccines or therapeutics. We discovered a novel class of small molecules ([1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones) with potent in vitro activity against CHIKV isolates from different geographical regions. Drug-resistant variants were selected and these carried a P34S substitution in non-structural protein 1 (nsP1), the main enzyme involved in alphavirus RNA capping. Biochemical assays using nsP1 of the related Venezuelan equine encephalitis virus revealed that the compounds specifically inhibit the guanylylation of nsP1. This is, to the best of our knowledge, the first report demonstrating that the alphavirus capping machinery is an excellent antiviral drug target. Considering the lack of options to treat CHIKV infections, this series of compounds with their unique (alphavirus-specific) target offers promise for the development of therapy for CHIKV infections. ; work was supported by the European Union Seventh Framework Program (FP7/2007–2013) under SILVER grant agreement (grant number 260644), EUVIRNA (grant agreement number 264286), BELSPO (IUAP-BELVIR), and the Spanish CICYT (SAF2012-39760-C02-01). L.D. is supported by a fellowship of the Fund for Scientific Research, Flanders (FWO). N.S.G. has been supported by the Doctoral Research Training Program “Francisco Jose de Caldas 494-2009” from Colombia and an ERACOL scholarship. A.G. has been supported by a JAEpredoctoral fellowship financed by the CSIC and the FSE (Fondo Social Europeo). ; Peer reviewed