The enyne-diyne [4+2] cross-benzannulation proceeded smoothly in the presence of Pd(0) catalyst to give 1,2,4-trisubstituted benzenes 8a-j, 1,2,3-trisubstituted benzenes 9a-i, 1,2,3,5-tetrasubstituted benzenes 11a-k, 1,2,3,4-tetrasubstituted benzenes 11l,m, and 1,2,3,4,5-pentasubstituted benzenes 11n-p in moderate to quantitative yields. In all cases the reaction was found to be regiospecific with regard to substitution at the benzene ring. The palladium-catalyzed [4+2] cycloaddition of monosubstituted conjugated enynes 3a-c and 5a with unsymmetrical diynes 13a-j and triynes 16a-g also proceeded with perfect regiochemistry with regard to substitution at the benzene ring. However, since two differently substituted triple bonds are present in the enynophiles 13 and 16, the enyne preference toward either triple bond in the enynophiles became an issue, and in most cases, two regioisomeric products were obtained. The detailed deuterium-labeling studies were performed, and the mechanism of this regiospecific [4+2] cycloaddition between enynes and diynes was proposed.