Abstract Fluorine is often used in drug-design efforts to enhance the pharmacokinetic properties of biologically active compounds. Additionally fluorine nuclei ( 19F) have properties that are well suited to current pharmaceutical NMR screening programs. Together, these considerations have motivated our interest in the utility of fluorine relaxation parameters to study ligand–receptor interactions. Here, we investigate the potential for cross-correlated relaxation effects between the 19F anisotropic chemical-shift and 19F– 1H dipole–dipole relaxation mechanisms to help pinpoint and quantify exchange processes. Methods are proposed and demonstrated in which the magnitude ratio of the transverse cross-correlation rate constant η xy and the fluorine transverse relaxation rate constant, R 2, help estimate the exchange rate constant for ligand-binding equilibria. These exchange rate constants provide estimates of the ligand dissociation rate constants k off and can thus provide a means for rank-ordering the binding affinities of ligands identified in pharmaceutical screens.