Empirical average proton-neutron interaction energies, delta V(pn), between the last nucleons can be isolated using double differences of masses. We have examined the systematic behavior of delta V(pn) throughout the mass surface using the 2003 mass table that includes many new and improved experimental masses. The results are especially revealing for self-conjugate nuclei and in regions of strong shell closures in heavy nuclei. In the former the large p-n interaction strength can be interpreted as a consequence of the T=0 interaction between protons and neutrons in spatially similar orbitals. In the latter, the bifurcated systematic can be understood in terms of the evolution of proton and neutron orbital overlaps in regions surrounding a shell closure. In regions between shells, anomalies are sometimes encountered that are not fully understood. They might reflect structural effects or could arise from one or more erroneously measured masses. A scheme based on fractional shell filling is presented that may serve as a signature of shell structure in exotic nuclei. A link between empirical p-n interactions and growth rates of collectivity is pointed out. Finally, our analysis is used to identify candidates for future mass measurements and their needed levels of accuracy, many of which will require new exotic beam facilities.