We will present a method1 that combines replica exchange2 with metadynamics3 and allows, with a moderate computational effort, the simultaneous reconstruction of the free energy as a function of a large number of variables. This allows simulating very complex reactions, like protein folding, in which the reaction coordinate is totally unknown. We will discuss applications of the methodology to protein folding, to amyloid aggregation, and to the study of drug-protein interaction. [1] S. Piana and A. Laio, J. Phys. Chem. B 111, 4553 (2007). [2] Y. Sugita and Y. Okamoto, Chem. Phys. Lett. 314, 141 (1999). [3] A. Laio and M. Parrinello, Proc. Natl. Acad. Sci. USA 99,12562 (2002).