In environments containing high energy density (HED) plasmas such as Inertial Confinement Fusion (ICF) or supernovae remnants, the Rayleigh-Taylor (RT) instability commonly occurs under large contrasts in density, temperature and fluid transport properties that scale strongly with temperature. In this dissertation, we examine highly resolved simulations of the 3D fully compressible RT instability at various temperature ratios and with different transport property configurations, providing a systematic analysis of how heat conduction, large variations in transport properties and sudden changes in transport properties can affect the development of a RT mixing layer.