We describe mosquito diversity, biogeography, and disease vector issues in the Grand Canyon (GC) region on the southern Colorado Plateau in northern Arizona. We detected the presence of 18 species from field collections and museum specimens from 1974–2005, including 10 new county records and two new regional records. Arizona State county records include a potential total of 24 species, while 32 species have been mapped as occurring in this region. The combined potential fauna is depauperate, a pattern consistent with that of low-vagility taxa in this large, deep canyon ecoregion. Culiseta incidens was by far the most common and widely distributed species (relative distributional frequency, RDF = 0.44), followed by Ochlerotatus epactius (0.12), Culex tarsalis (0.09), Culiseta inornata (0.08), and Anopheles franciscanus (0.06); all other species were rare (RDF ≤ 0.05). The diversity of detected species was non-linearly related to elevation, with six species distributed widely across elevation, five species found below 1800 m, and seven species occurring above 1800 m. The potential and detected fauna is dominated (44.7–61.1 percent) by Mexican and neotropical taxa, with a lower diversity of indigenous and boreal-palearctic species. The proportion of Mexican taxa in the GC region remains equivalent to that in southern Arizona, but GC has more palearctic taxa and fewer neotropical taxa. Several species may vector avian, livestock, and human diseases, including West Nile virus (WNV), including Culex spp. (widespread) and Aedes vexans (low elevations), while Ochlerotatus epactius, Oc. cataphylla, Anopheles hermsi, and Cx. erythrothorax occasionally are locally pestiferous. While abundant, Cs. incidens is regarded as having a low vector competence for WNV.