Hydrodesulfurization (HDS) catalysts have been extensively used worldwide in refineries to protect the environment. The present Account reviews our recent studies to establish the structureactivity relationships of HDS catalysts on a molecular level. We have developed two molecular approaches to this issue; a molecular cluster approach using intrazeolite Mo sulfide and CoMo binary sulfide clusters possessing well-defined structures and a CVD-CoMo sulfide designed catalyst approach in which Co is exclusively accommodated in the CoMoS structure, the active sites of HDS catalysts. It is revealed that the Co sites of intrazeolite thiocubane-type [Co 2 Mo 2 S 6 ] clusters play a pivotal role in HDS reaction and that the MoMo atomic distance of Mo 2 S 4 dinuclear clusters determines the HDS activity. Designed CVDCoMo catalysts supported on refractory oxides have been successfully prepared by CVD using [Co(CO) 3 NO] as a precursor of Co. Combined with magnetic properties and XAFS, it is concluded that the CoMoS structure is dinuclear Co sulfide clusters located on the edge of MoS 2 nanoparticles. It is shown that the intrinsic activity of the CoMoS structure substantially depends on the MoS 2 -edge where it is located. The effects of support and additives are discussed on the basis of the intrinsic activity. Both MoS 2 support interactions and reaction or sulfidation conditions elucidate the local structure and intrinsic activity of the CoMoS structure. It is demonstrated that the CVD technique using [Co(CO) 3 NO] provides unique characterization methods of HDS catalysts.