The West Nile virus (WNV) may post a significant health risk for mammals, including humans and insects. This study examines the spatial-temporal effects of environmental factors on WNV dissemination with a case study of ten counties in the southern California, where the epidemic was recently most prevalent within the USA. WNV surveillance data were obtained from the California Vectorborne Disease Surveillance System and Centers for Disease Control and Prevention. Remote sensing and Geographic Information Systems (GIS) techniques were combined to derive environmental variables. Principal component analysis was performed to select the most relevant environmental variables. Two ecological zones were identified based on the selected variables. Identification of risk areas for WNV was limited to a zone with 95% mosquitoes surveillance records. Three time windows, the epidemiological weeks 18-26, 27-35, and 36-44 in each year of 2007-2009, were examined in details with risk area mapping. It is found that the southern part of San Joaquin Valley in Kern County and Los Angeles County (especially its southern part) were the most vulnerable locations for WNV outbreak. Main factors contributing to the WNV propagation included summer mean temperature, annual mean deviation from the mean temperature, land surface temperature, elevation, landscape complexity, landscape diversity, and vegetation water content. The result of this study improves understanding of WNV ecology and provides tools for detecting, tracking, and predicting the epidemic. The holistic approach developed for this study, which integrated remotely sensed, GIS-based, and in situ-measured environmental data with landscape metrics, may be applied to studies of other vector-borne diseases.