A model is presented to explain catecholamine uptake into isolated chromaffin granules and ghosts. It is based on the following observations and conclusions: 1) the chromaffin granule maintains one of the lowest permeabilities to cations of any previously isolated subcellular organelle and the lowest permeability to protons, 2) a transmembrane proton gradient delta pH exists across the chromaffin granule membrane that is not media dependent, with a measured internal pH of 5.5; 3) the addition of ATP to a suspension of chromaffin granules results in the generation of a membrane potential of 80-100 mV, positive inside; 4) an H+-translocating ATPase responsible for the generation of this electrochemical proton gradient (delta micro H+) exists within the membrane of the chromaffin granule; 5) net amine accumulation proceeds in the presence of both a delta pH alone and a transmembrane potential gradient delta psi alone, with the maximal rate and extent occurring in the presence of a delta pH and a delta psi together (delta micro H+); 6) when catecholamine uptake is in equilibrium with the delta micro H+, the equilibrium distribution of amines (delta micro A) obeys the relationship delta micro A = delta psi-2Zdelta pH. The model, in its elemental form, states that an H+-translocating ATPase for the generation of a delta pH and delta psi exists within the membrane of the chromaffin granule. This electrochemical proton gradient provides the driving force for amine influx, which proceeds via a reserpine-sensitive antiport carrier mechanism coupled to proton efflux. The model is discussed in terms of its physiological implications and significance for other amine-containing subcellular organelles, with particular respect to the species of catecholamine transported, and other unresolved issues.