The Mediterranean cypress (Cupressus sempervirens) is an evergreen conifer that belongs to the Cupressaceae, which is the first plant family whose detailed evolutionary history traces the break-up of the supercontinent Pangaea roughly 150 million years ago. The broad and deep economic and socio-cultural significance of the species began in at least the third millennium BCE. This interdisciplinary review highlights the tree’s exemplary uses and meanings, starting in ancient Elam, Sumer, Egypt, and Persia, and continuing to the Graeco-Roman world, Islamic Empires, and Western Europe. The Mediterranean cypress has been used as timber for buildings, coffins, furniture, and statuary; in religious and spiritual symbolism; as ornamentals in gardens and cemeteries; in aromatic anointments and medicine; as literary metaphors; and as motifs in decorative and fine art. Many of the artifacts, artworks, and literature known to be influenced by the cypress are iconic: the Gudea cylinders, the outer coffin of Pharaoh Tutankhamun, the poetry of Virgil and Ferdowsi, Istanbul’s Topkapi Palace, Shakespeare’s plays, and the paintings of Vélasquez and Van Gogh. Knowledge gaps in the scholarly literature on the species are identified, which require additional research in a variety of fields. For example, the number of varieties within the species remains inconclusive. Identifying the precise timing and geographic location of the tree’s influence on human civilization is hampered by methodological challenges. Studies of other plant species might benefit from the holistic approach taken in this review.