Alphaviruses are members of the Togaviridae family and are grouped into two categories: arthritogenic and encephalitic. Arthritogenic alphavirus infections, as the name implies, are associated with arthritic outcomes while encephalitic alphavirus infections can lead to encephalitic outcomes in the infected host. Of the non-structural proteins (nsPs) that the viruses code for, nsP3 is the least understood in terms of function. Alphavirus nsP3s are characterized by regions with significantly conserved domain structure along with regions of high variability. Interactions of nsP3 with several host proteins have been documented including, stress granule-related proteins, dead box proteins, heat shock proteins, and kinases. In some cases, in addition to the interaction, requirement of the interaction to support infection has been demonstrated. An understanding of the proteomic network of nsP3 and the mechanisms by which these interactions support the establishment of a productive infection would make alphavirus nsP3 an interesting target for design of effective medical countermeasures.