Calixarenes are used as molecular scaffolds for the preparation of novel receptors for cations, anions, and neutral molecules. Although widely studied, the nature of the host-guest interactions within these molecules remains obscure. We present a combined density-functional theory and second-order perturbation theory study of the complexation of the alkali cations Na+ and Cs+ with tetramethoxycalix[4]arene. The results show that the host-guest interactions of this simple system are much more complex than previously thought and suggest new approaches for the design of selective cation receptors.