The Sonoran Desert is a large, flat, pseudo-invariant site near the United States-Mexico border. It is one of the largest and hottest deserts in North America, with an area of 311,000 square km. This site is particularly suitable for calibration purposes because of its high spatial and spectral uniformity and reasonable temporal stability. This study uses measurements from four different sensors, Terra Moderate Resolution Imaging Spectroradiometer (MODIS), Landsat 7 (L7) Enhanced Thematic Mapper Plus (ETM+), Aqua MODIS, and Landsat 5 (L5) Thematic Mapper (TM), to assess the suitability of this site for long-term stability monitoring and to evaluate the “radiometric calibration differences” between spectrally matching bands of all four sensors. In general, the drift in the top-of-atmosphere (TOA) reflectance of each sensor over a span of nine years is within the specified calibration uncertainties. Monthly precipitation measurements of the Sonoran Desert region were obtained from the Global Historical Climatology Network (GHCN), and their effects on the retrieved TOA reflectances were evaluated. To account for the combined uncertainties in the TOA reflectance due to the surface and atmospheric Bi-directional Reflectance Distribution Function (BRDF), a semi-empirical BRDF model has been adopted to monitor and reduce the impact of illumination geometry differences on the retrieved TOA reflectances. To evaluate calibration differences between the MODIS and Landsat sensors, correction for spectral response differences using a hyperspectral sensor is also demonstrated.