The atom-centered partial charges-approximation is commonly used in current molecular modeling tools as a computationally inexpensive alternative to quantum mechanics for modeling electrostatics. Even today, the use of partial charges remains useful despite significant advances in improving the efficiency of ab initio methods. Here, we report on new parameters for the EEM and SFKEEM electronegativity equalization-based methods for rapidly determining partial charges that will accurately model the electrostatic potential of flexible molecules. The developed parameters cover most pharmaceutically relevant chemistries, and charges obtained using these parameters reproduce the B3LYP/cc-pVTZ reference electrostatic potential of a set of FDA-approved drug molecules at best to an average accuracy of 13 +/- 4 kJ mol(-1); thus, equipped with these parameters electronegativity equalization-based methods rival the current best non-quantum mechanical methods, such as AM1-BCC, in accuracy, yet incur a lower computational cost. Software implementations of EEM and SFKEEM, including the developed parameters, are included in the conformer-generation tool BALLOON, available free of charge at http://web.abo.fi/fak/mnf/bkf/research/johnson/software.php. Copyright 2009 Wiley Periodicals, Inc.