Experimental infection studies with bluetongue virus (BTV) in the mammalian host have a his-tory that stretches back to the late 18th century. Studies in a wide range of ruminant and camelidspecies as well as mice have been instrumental in understanding BTV transmission, bluetongue (BT)pathogenicity/pathogenesis, viral virulence, the induced immune response, as well as reproductive fail-ures associated with BTV infection. These studies have in many cases been complemented by in vitrostudies with BTV in different cell types in tissue culture. Together these studies have formed the basisfor the understanding of BTV-host interaction and have contributed to the design of successful controlstrategies, including the development of effective vaccines. This review describes some of the fundamen-tal and contemporary infection studies that have been conducted with BTV in the mammalian host andprovides an overview of the principal animal welfare issues that should be considered when designingexperimental infection studies with BTV in in vivo infection models. Examples are provided from theauthors’ own laboratory where the three Rs (replacement, reduction and refinement) have been imple-mented in the design of experimental infection studies with BTV in mice and goats. The use of the ARRIVEguidelines for the reporting of data from animal infection studies is emphasized.