Using molecular dynamics and thermodynamic integration, we report on the solvation process of seven polypeptides (GLY, ALA, ILE, ASN, LYS, ARG, GLU) in water and in cyclohexane. The polypeptides are selected to cover the full hydrophobic scale while varying their chain length from tri- to undeca-homopeptides, providing indications on possible non-additivity effects as well as the role of the peptide backbone in the overall stability of the polypeptides. The use of different solvents and different polypeptides allows us to investigate the relation between solvent quality – the capacity of a given solvent to fold/unfold a given biopolymer often described on a scale ranging from “good” to “poor”; and solvent polarity – related to the specific interactions of any solvent with respect to a reference solvent. Undeca-glycine is found to be the only polypeptide to have a stable collapse in water (polar solvent), with the other hydrophobic polypeptides displaying repeated folding and unfolding events in water, with polar polypeptides presenting even more complex behavior. By contrast, all polypeptides are found to keep an extended conformation in cyclohexane, irrespective of their polarity. All considered polypeptides are also found to have favorable solvation free energy independent of the solvent polarity and their intrinsic hydrophobicity, clearly highlighting the prominent stabilizing role of the peptide backbone – with the solvation process largely enthalpically dominated in polar polypeptides and partially entropically driven for hydrophobic polypeptides. Our study thus reveals the complexity of the solvation process of polypeptides defying the common view “like dissolves like”, with the solute polarity playing the most prominent role. The absence of mirror symmetry upon the inversion of polarities of both the solvent and the polypeptides is confirmed.