Naturally occurring cellulose is crystalline as a consequence of the strong interactions between the glucan chains that comprise it and therefore is insoluble in most solvents. One of the few solvent systems able to dissolve cellulose is lithium chloride (LiCl) dissolved in N,N-dimethylacetamide (DMA). By an integrated application of all-atom molecular dynamics (MD) simulations, reaction path optimization, free-energy calculations, and a force-matching analysis of coarse-grained atomistic simulations, we establish that DMA-mediated preferential interactions of Li+ cations and CL- anions with glucan chains enable cellulose dissolution in LiCl/DMA. The relatively weak solvation of Li+, Cl-, and glucan chains by DMA results in strong effective interactions of Li+ and Cl- ions with the glucans, leading to cellulose dissolution. The small size of the Li+ cations allows them to strongly couple to multiple interaction sites on the glucan chains of cellulose, including the spatially restricted regions around the ether linkages connecting neighboring glucose residues. Li+ cations were thus identified as the main component responsible for driving cellulose dissolution. The mechanism for explaining the solubility of cellulose in the LiCl/DMA system deduced from the analysis of atomistic-scale simulations conducted in this work is also consistent with most of the empirical observations related to cellulose dissolution in salt/amide solvent systems.