<p>ODE simulations of chemical systems perform poorly when some of the species have extremely low concentrations. Stochastic simulation methods, which can handle this case, have been impractical for large systems due to computational complexity. We observe, however, that when modeling complex biological systems: (1) a small number of reactions tend to occur a disproportionately large percentage of the time, and (2) a small number of species tend to participate in a disproportionately large percentage of reactions. We exploit these properties in LOLCAT Method, a new implementation of the Gillespie Algorithm. First, factoring reaction propensities allows many propensities dependent on a single species to be updated in a single operation. Second, representing dependencies between reactions with a bipartite graph of reactions and species requires only <inline-formula><inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="info:doi/10.1371/journal.pone.0008125.e001" mimetype="image" xlink:type="simple"/></inline-formula> storage for <inline-formula><inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="info:doi/10.1371/journal.pone.0008125.e002" mimetype="image" xlink:type="simple"/></inline-formula> reactions, rather than the <inline-formula><inline-graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="info:doi/10.1371/journal.pone.0008125.e003" mimetype="image" xlink:type="simple"/></inline-formula> required for a graph that includes only reactions. Together, these improvements allow our implementation of LOLCAT Method to execute orders of magnitude faster than currently existing Gillespie Algorithm variants when simulating several yeast MAPK cascade models.</p>