Puupehenones have been isolated from the marine sponge Chondrosia chucalla, which belong to a growing family of natural products with more than 100 members. These marine natural products have attracted increasing attention mainly due to their wide variety of biological activities such as antitumor, antiviral, and anti-HIV, and thus offer promising opportunities for new drug development. This chapter covers the approaches to the total synthesis of puupehenone-type marine natural products including puupehenol, puupehenone, puupehedione, and halopuupehenones. The routes begin with the construction of their basic skeletons, followed by the modification of their C-and D-rings. The contents are divided into two sections in terms of the key strategies employed to construct the basic skeleton. One is the convergent synthesis route with two synthons coupled by nucleophilic or electrophilic reaction, and the other is the linear synthesis route with polyene series cyclization as a key reaction.