A key property in all lignin valorization processes is the solubility of lignin in different solvents. Therefore, understanding the fundamentals, i.e. the solubility mechanisms from a physicochemical point of view at the atomistic level, is of great importance. Solubility is related to the free energy of solvation, which is a sum of changes in enthalpy and entropy when transferring a molecule from vapor phase into solution. Investigating the solubility through solvation free energies of lignin molecules with varying chemical structure and molecular weight provide insights into solvent-exchange scheme in nanoparticle fabrication, fractionation of lignin samples and even diffusion rate of lignin in the cell wall. [1,2,3]Molecular dynamics (MD) simulations in GROMACS were used to calculate the free energy of solvation of lignin molecules in water and organic solvents. [4] In alchemical free energy of solvation calculations, a series of nonphysical intermediates is used to move the molecule from gas phase to solution. This is done by perturbing the interactions between solute and solvent going between state A of no interactions to state B of all interactions. Using water as a reference, the free energy of solvation of lignin can be compared between various organic solvents and water. [5,6]The results confirm the experimental results of higher solubility of lignin in the organic solvents ethanol, acetone, tetrahydrofurane and dimethylsulfoxide compared with water. [7] Additionally, the entropic and enthalpic contributions show differences between the organic solvents. There is also a dependence on linkage type between the monolignol units, as well as the molecular weight of the molecule. This method provides detailed insights into the dependence of solvent, chemical structure and molecular weight on the solubility of lignin.