The review covers the literature on the total synthesis of cross-conjugated cyclopentenone prostaglandins (PGs), published from 2000 until present. In view of the specific features differentiating cyclopentenone PGs from prostaglandins of other types, special attention in the review is focused on the biochemistry and physiological functions of the most important representatives of cyclopentenone PGs. Data on analogs of cyclopentenone PGs are presented, and certain aspects of structure–activity correlations and potential practical applications of these compounds are discussed.