The host factors required for entry of arthritogenic alphaviruses, such as Chikungunya virus (CHIKV), remain poorly characterized. Using a genome-wide CRISPR–Cas9-based screen in mice, Zhang et al. identified the host cell adhesion molecule MXRA8 as a mediator of CHIKV entry. Further studies in mouse and human cell lines revealed MXRA8 to be required for infection by multiple other arthritogenic alphaviruses. Mechanistically, MXRA8 bound directly to CHIKV particles, which enhanced virus attachment and internalization into cells. Injection of mice with anti-MXRA8 blocking antibodies reduced CHIKV and O'nyong nyong virus titres and decreased foot swelling.