The origins of reactivity and regioselectivity in nickel-catalyzed reductive coupling reactions of alkynes and aldehydes were investigated with density functional calculations. The regioselectivities of reactions of simple alkynes are controlled by steric effects, while conjugated enynes and diynes are predicted to have increased reactivity and very high regioselectivities, placing alkenyl or alkynyl groups distal to the forming C−C bond. The reactions of enynes and diynes involve 1,4-attack of the Ni−carbonyl complex on the conjugated enyne or diyne. The consequences of these conclusions on reaction design are discussed.