Covering: 2000-2020The 1,4-diene motif, also known as a skipped diene, is widespread across various classes of natural products including alkaloids, fatty acids, terpenoids, and polyketides as part of either the finalized structure or a biosynthetic intermediate. The prevalence of this nonconjugated diene system in nature has resulted in numerous encounters in the total synthesis literature. However, skipped dienes have not been extensively reviewed, which could be attributed to overshadowing by the more recognized 1,3-diene system. In this review, we aim to highlight the relevance of skipped dienes in natural products through the lens of total synthesis. Subjects that will be covered include nomenclature, structural properties, prevalence in natural products, synthetic strategies and the future direction of the field.