Daxx is an ubiquitous protein that was first identified as a Fas-interacting protein. Although cytoplasmic Daxx is involved in apoptosis, it is predominantly a nuclear protein. In the nucleus, Daxx is mainly located within PML nuclear bodies (PML NBs), nuclear structures involved in many cellular processes. The main function of Daxx in the nucleus is transcriptional repression through interactions with multiple factors involved in transcription. Daxx, like other PML NB resident proteins, such as PML itself, but also Sp100 and ATRX, is involved in antiviral defense. In concordance with this, many viruses target Daxx to replicate. Daxx-induced viral restriction has been particularly studied in the case of herpesviruses and adenoviruses, but recent findings suggest that Daxx also has a major role in the replication of retroviruses, including HIV-1. In this review, we summarize and discuss the different antiviral activities of Daxx and detail the strategies that viruses have evolved to escape.