Two divergent and complementary methodologies for preparing neopentylene-tethered (NPT) 1,6-diynes are described. These NPT 1,6-diynes are valuable π-systems for reaction discovery and building blocks for target-oriented synthesis. Ring-opening fragmentation of dimedone (and alkylation) produces alkyne-tethered β-keto esters 6. One-pot dehydration with optional saponification produces diyne monoester 15 or monoacid 3, which can be further functionalized using traditional alkyne substitution chemistry and/or carboxylate manipulations. For example, copper-catalyzed decarboxylation of acid 3 provides 4,4-dimethyl-1,6-heptadiyne (1), now in ca. 76% yield over four steps from dimedone. A complementary approach using Zard fragmentation chemistry converts alkylated β-keto esters into the corresponding monoalkylated NPT 1,6-diynes. The utility of substituted NPT 1,6-diynes in target-oriented synthesis is noted herein.