Many molecular simulation force fields represent the charge distributions of molecules with atom-centered partial charges, so simulations with these force fields require that partial charges be assigned to the molecules of interest. The restrained electrostatic potential (RESP) approach is a highly regarded and widely used method of assigning partial charges to varied organic compounds. RESP uses gas-phase HF/6-31G* as the underlying quantum chemical method, intending the resulting overpolarization of molecules to approximate the self-polarization that occurs in the condensed phase setting. However, it is far from clear that this fortuitous overpolarization is optimal or consistent across all compounds. In order to reach a higher level of accuracy, we propose a next generation of this approach, termed RESP2. In RESP2, the charges are derived from higher-level quantum chemical calculations carried out for both gas and aqueous phase, the latter using a continuum solvent model. The polarity of the final charges is tuned by a mixing parameter, δ, which scales the relative contributions of the gas- and aqueous-phase charges. We find that simply substituting RESP2 charges for RESP charges in the context of regular LJ parameters does not lead to clear improvement in liquid-state densities and heats of vaporization but does improve the accuracy of observables expected to depend most strongly on the accuracy of the charge model, i.e., dielectric constants and molecular dipole moments. However, when Lennard-Jones (LJ) parameters are optimized in the context of RESP charges, based on liquid properties, significant improvement in accuracy can be achieved, even with a sharply reduced set of LJ types. We argue that RESP2 with δ≈0.6 (60% aqueous and 40% gas-phase charges) is an accurate and robust method of generating atom-centered partial charges. The present study also highlights the value of optimizing LJ parameters along with the electrostatic model and suggests that a small set of LJ types can be a good starting point for a systematic re-optimization of this important nonbonded term.