The solubility of organic molecules is a well established property, founded on decades of measurements, the results of which have been tabulated in handbooks. Under atmospheric conditions water droplets may form containing small amounts of other molecules. Such droplets typically have a very large area to volume ratio, which may shift the solvation equilibrium towards molecules residing on the droplet surface. The presence of organic molecules on droplet surfaces is extremely important for reactivity – it is well established that certain chemical reactions are more prevalent under atmospheric conditions than in bulk. Here we present a thermodynamic rationalization of the surface solvation properties of methanol, ethanol, propanoic acid, n-butylamine, diethyl ether, and neopentane based on potential of mean force (PMF) calculations – we have previously demonstrated that an energetic description is a very powerful means of disentangling the factors governing solvation (Caleman et al., Proc. Natl. Acad. Sci. U. S. A., 2011, 108, 6838–6842). All organic molecules investigated here are preferentially solvated on the surface of the droplets rather than in the inside, yet the magnitude of surface preference may differ by orders of magnitude. In order to dissect the energetic contributions that govern surface preference, we decompose the PMF into enthalpic and entropic components, and, in a second step, into contributions from water–water and solute–water interactions. The analysis demonstrates that surface preference is primarily an enthalpic effect, but the magnitude of surface preference of solutes containing large apolar groups is enhanced due to entropy. We introduce an analysis of the droplet PMFs that allows one to extrapolate the results to larger droplets. From this we can estimate the solubility of the solutes in water droplets, demonstrating that the solubility in droplets can be orders of magnitude larger than in bulk water. Our findings have implications for understanding the process of electrospray ionization, an important technique in biological mass spectrometry, since our work strongly suggests that in equilibrium biomolecules would be adsorbed on the droplet surface as well.