The molecular mechanism of osmolytes on the stabilization of native states of protein is still controversial irrespective of extensive studies over several decades. Recent investigations in terms of experiments and molecular dynamics simulations challenge the popular osmophobic model explaining the mechanistic action of protein-stabilizing osmolytes. The current Perspective presents an updated view on the mechanistic action of osmolytes in light of resurgence of interesting experiments and computer simulations over the past few years in this direction. In this regard, the Perspective adopts a bottom-up approach starting from hydrophobic interactions and eventually adds complexity in the system, going toward the protein, in a complex topology of hydrophobic and electrostatic interactions. Finally, the Perspective unifies osmolyte-induced protein conformational equilibria in terms of preferential interaction theory, irrespective of individual preferential binding or exclusion of osmolytes depending on different osmolytes and protein surfaces. The Perspective also identifies future research directions that can potentially shape this interesting area.