Domestic arthropod-borne viruses (arboviruses) are single-stranded RNA viruses, the most common of which include the mosquito-borne West Nile virus, St. Louis encephalitis virus, La Crosse virus, Jamestown Canyon virus, and eastern equine encephalitis virus, as well as the tick-borne Powassan virus. Previously con sidered rare infections, they have been detected with increasing frequency over the past 2 decades. Here, we present an overview of the domestic arboviruses listed above and describe the modalities employed to diagnose infection. Global arboviruses, including dengue virus, Zika virus, and chikungunya virus, have also been increasingly detected in the United States within the last 5 years but are not a focus of this minireview. Typical manifestations of arbovirus infection range from no symptoms, to meningitis or encephalitis, to death. Serologies are the standard means of diagnosis in the laboratory, since most viruses have a short period of replication, limiting the utility of molecular tests. The interpretation of serologies is confounded by antibody cross-reactivity with viruses belonging to the same serogroup and by long-lasting antibodies from prior infections. Next-generation assays have improved performance by increasing antigen purity, selecting optimal epitopes, and improving interpretive algorithms, but challenges remain. Due to cross-reactivity, a positive first-line serology test requires confirmation by either a plaque reduction neutralization test or detection of seroconversion or a 4-fold rise in virus-specific IgM or IgG antibody titers from acuteand convalescent-phase sera. The use of molecular diagnostics, such as reverse transcription PCR or unbiased metagenomic sequencing, is limited to the minority of patients who present with ongoing viremia or central nervous system replication. With the continued expansion of vector range, the diagnosis of domestic arboviruses will become an increasingly important task for generalists and specialists alike.