Terpene synthases often catalyze complex reactions involving intricate series of carbocation intermediates. The resulting, generally cyclical, structures provide initial hydrocarbon frameworks that underlie the astonishing structural diversity of the enormous class of terpenoid natural products (>50,000 known), and these enzymes often mediate the committed step in their particular biosynthetic pathway. Accordingly, how terpene synthases specify product outcome has drawn a great deal of attention. In previous work, we have shown that mutational introduction of a hydroxyl group at specific positions within diterpene synthase active sites can "short circuit" complex cyclization and/or rearrangement reactions, resulting in the production of "simpler"' diterpenes. Here we demonstrate that the converse change, substitution of an Ile for Thr at the relevant position in a native pimaradiene synthase, leads to a dramatic increase in reaction complexity. Product outcome is shifted from the tricyclic pimaradiene to a rearranged tetracycle, aphidicol-15-ene. Thus, the nature of the residue at this position acts as a true switch for product outcome. In addition, the ability of aliphatic residue substitution to enable a more complex reaction emphasizes the importance of substrate conformation imposed by a largely inert active site. Furthermore, the profound plasticity of diterpene synthases exemplified by this single residue switch for product outcome is consistent with the screening/diversity-oriented hypothesis of natural products metabolism.