The ability to predict spectral electro-optical (EO) signatures for various targets against realistic, cluttered backgrounds is paramount for rigorous signature evaluation. Knowledge of background and target signatures, including plumes, is essential for a variety of scientific and defense-related applications including contrast analysis, camouflage development, automatic target recognition (ATR) algorithm development and scene material classification. The capability to simulate any desired mission scenario with forecast or historical weather is a tremendous asset for defense agencies, serving as a complement to (or substitute for) target and background signature measurement campaigns. In this paper, a systematic process for the physical temperature and visible-through-infrared radiance prediction of several diverse targets in a cluttered natural environment scene is presented. The ability of a virtual airborne sensor platform to detect and differentiate targets from a cluttered background, from a variety of sensor perspectives and across numerous wavelengths in differing atmospheric conditions, is considered. The process described utilizes the thermal and radiance simulation software MuSES and provides a repeatable, accurate approach for analyzing wavelength-dependent background and target (including plume) signatures in multiple band-integrated wavebands (multispectral) or hyperspectrally. The engineering workflow required to combine 3D geometric descriptions, thermal material properties, natural weather boundary conditions, all modes of heat transfer and spectral surface properties is summarized. This procedure includes geometric scene creation, material and optical property attribution, and transient physical temperature prediction. Radiance renderings, based on ray-tracing and the Sandford-Robertson BRDF model, are coupled with MODTRAN for the inclusion of atmospheric effects. This virtual hyperspectral/multispectral radiance prediction methodology has been extensively validated and provides a flexible process for signature evaluation and algorithm development.