We report substituent effects on conformational preferences and hole mobilities of 2,5-bis-(thiophen-2-yl)thieno[ 3,2-b] thiophenes (BTTT) monomer and dimer, and hexyl derivatives. We employ single-crystal X-ray diffraction, quantum mechanical calculations, and thin-film transistors to explore the difference between monomer, dimer, and effect of hexyl substitution. The hexyl-substituted molecules show marked differences in solid-state packing compared to the unsubstituted analogs. Most notably, the alkylated monomer crystal structure exhibits terminal thiophenes in the syn conformation. In contrast, the unsubstituted monomer adopts the more common anti conformation. The hexyl-substituted dimer, however, features a mixture of syn and anti thiophenes. Gas phase conformations of oligomers rationalize the intrinsic conformational preferences. We use a multimode simulation to compute hole mobilities and find excellent agreement with experiment. Theoretical results support our hypothesis that alkyl side chains cause these small molecules to adopt orientations that enhance hole mobilities by an order of magnitude upon hexyl substitution of the monomer.