Driven by the growing demand for ultra-clean fuels and the increasing use of low-quality crudes/feedstocks, sulfur removal from hydrocarbon feedstocks has received and will continue to attract much attention in the coming years. Tremendous efforts have been expended on the discovery and development of new catalysts for catalytic hydrodesulfurization (HDS). Deep HDS catalysts are required to perform two functions: hydrogenation and hydrogenolysis. This talk addresses limiting factors bearing on the chemistry and catalysis in deep HDS. Among the discussion topics are reactivity-property relationships, catalyst functionalities, organonitrogen inhibiting effects, nature of active sites, quantification of active sites via transient experiments, and hydrogenation-hydrogenolysis tradeoff. It is shown that combined model-compound and real-feed experiments provide insights that are otherwise unobtainable. Examples are given to demonstrate how the hydrogenation-hydrogenolysis tradeoff can be exploited for catalyst-process optimization.