Replica exchange (RE) is a generalized ensemble simulation method for accelerating the exploration of free-energy landscapes which define many challenging problems in computational biophysics, including protein folding and binding. Although replica exchange is a parallel simulation technique whose implementation is relatively straightforward, kinetics and the approach to equilibrium in the replica exchange ensemble are complicated; there is much to learn about how to best employ RE to protein folding and binding problems. Protein folding rates often slow down as the temperature is raised above a critical value and this “anti-Arrhenius” behavior represents a challenge for RE. However, it is far from straightforward to systematically explore the impact of this on RE by brute force molecular simulations, since RE simulations of protein folding are very difficult to converge. In studies over the past two years using both atomistic and simplified models, we have clarified some of the obstacles to obtaining converged thermodynamic information from RE simulations. In my talk I will describe some simple continuous and discrete models we have constructed to explore the behavior of replica exchange sampling under a variety of conditions. References Andrec, M., A.K. Felts, E. Gallicchio, and R.M. Levy. Protein folding pathways from replica exchange simulations and a kinetic network model. Proceedings Natl. Acad. Sci. USA, 102, 6801-6806 (2005). K.P. Ravindranathan, E. Gallicchio, R.A. Friesner, A.E. McDermott, and R.M. Levy. Conformational equilibrium of a cytochrome P450 – substrate complex, a replica exchange MD study. J. Am. Chem. Soc., 128, 5786-5791 (2006) Zheng, W., M. Andrec, E. Gallicchio, and R.M. Levy. Simulating replica exchange simulations of protein folding with a kinetic network model. Proceedings Natl. Acad. Sci. USA, 104, 15340-15345 (2007). Zheng, W., M. Andrec, E. Gallicchio, and R.M. Levy. Simple continuous and discrete models for simulating replica exchange simulations of protein folding. J. Phys. Chem., in press.