Transition metal-catalyzed [m+n+o] carbocyclization reactions provide powerful methods for the construction of complex polycyclic systems that are generally not accessible through classical pericyclic reactions. We have developed the first regio- and enantioselective crossed intermolecular rhodium-catalyzed [2+2+2] carbocyclization of carbon- and heteroatom-tethered 1,6-enynes with unsymmetrical 1,2-disubstituted alkynes. This study clearly delineates the ligand requirements for obtaining excellent regio- and enantioselectivity. Furthermore, the ability to utilize various electron-withdrawing groups, and to introduce quaternary carbon stereogenic centers, provides the level of versatility necessary for its application to target-directed synthesis. Additional studies on the development and application of this novel methodology to the total synthesis of natural products are currently underway.