Pillararenes, a recently discovered class of aromatic macrocycles, form inclusion complexes with a large number of guest molecules, but not much is known about the driving forces of complexation, including the role of the solvent. We have measured the binding thermodynamics for a small number of model complexes in several solvents and used computational chemistry to rationalize the obtained results and identify the driving forces of complexation. Favorable electrostatic interactions between the host and guest are obtained when the charge distribution in the guest matches the negative electrostatic potential in the cavity of the pillararene. Polar guests, however, also interact strongly with polar solvents, thereby shifting the complexation equilibrium away from the complex. The shape of the solvent molecules is another important factor as some solvents are sterically hindered from entering the pillararene cavity. By changing solvent from acetonitrile to o-xylene the binding constant in one case increased more than 4 orders of magnitude. Even electrostatically similar solvents such as o-xylene and p-xylene have very different impacts on the binding constants due to their different abilities to fit into the cavity. The study illustrates the importance of taking into account the interactions between the solvent and the complexing species in the investigation and design of molecular host:guest systems.