The potential scientific and technological solutions to the problems that appear as a result of shifting the hydrotreating of crude oil middle distillates and shale oils from the ’normal’ to the ’deep’ mode are considered on the basis of the reactivities and transformation routes of the least-reactive sulfur-, nitrogen-, and oxygen-containing compounds. The efficiency of selecting the optimal feedstock, increasing the process severity, improving the catalysts activity, and using alternative catalytic routes are compared, taking into account the specific issues related to deep hydrodesulfurization/hydrodenitrogenation/hydrodeoxygenation, i.e., chemical aspects, kinetics and catalysts.