The perceived phobia (fear) of some apolar substances for aqueous (hydro) environments does not imply lack of attraction to water. Rather, it originates from the strength of this attraction, which, similar to that between the constituents of apolar substances, is smaller than the force between water molecules. Fear of those who dominate the scene (in this case, water hydrogen bonds) is hardly surprising. The concept of hydrophobicity, intuitively associated with the demixing of oil and water, appears in most biophysics and biochemistry textbooks, and it is generally accepted that hydrophobic interactions are a major driving force of fundamental biological processes, for example, protein folding, molecular recognition, and the formation of membranes (1,2). Yet, the molecular theory of the hydrophobic effect and the microscopic understanding of the hydration of hydrophobic species (or hydrophobic hydration), are incomplete. The article by Li et al. (3) in this issue of PNAS presents the first investigation of hydrophobic association for a model system (two methane molecules in water) entirely based on first principles, i.e., on a quantum mechanical description of electronic and electron–ion interactions (4) of the combined solute–solvent system. The potential of mean force between the two methane molecules computed in ref. 3 is consistent with the data extracted from several hydrocarbon solubility experiments, but it is substantially different from what is found in simulations based on empirical classical force fields. These simulations represent the majority of computer simulations carried out in the last 30 years to investigate hydrophobic effects at the microscopic level. The results of ref. 3 indicate that these empirical simulations may lead to an underestimation of the hydrophobic effect in many instances, and they point to the need for an accurate, ab …