This paper attempts to reconstruct the evolution of the Salpi lagoon during the Holocene. The authors examined archaeological evidence and historical documents supplemented by field data. The research highlights the role of climatic variations and human interference in evolution of the lagoon. The data collected show that: • At the beginning of the Holocene the sea level rise caused the development of a sandy barrier between Gargano Headland and Murge. This barrier enclosed a wide coastal lagoon, called "Laguna di Salpi". • Favourable environmental conditions permitted human occupation on the inner side of the lagoon during the early Neolithic by populations coming from the eastern coasts of the Adriatic Sea. • At the end of the Neolithic the lagoon evolved into a sabkha and the whole area was abandoned until end of the 3rd millennium B.C. • Between the III and I millennium B.C. the lagoon, communicating by several entrances with the sea , was deep enough for navigation. • Between the II and I century B.C. the Tavoliere coastal area was affected by malaria and the lagoon settlements were abandoned. • During the Middle Ages the Tavoliere coastal plain was almost depopulated, whereas the area around the lagoon was densely inhabited. • Despite many attempts at reclamation during the Modern Age the whole Tavoliere was a malarial area. • The lagoon then turned into a large coastal swamp which survived up to the 1930s when, after the "Serpieri Iandolo" law, radical reclamation activities began. • Two areas of the ancient Holocene lagoon still survive: the first is a swamp called Palude Frattarolo, the second is an area dedicated to salt production, called Saline di Margherita di Savoia.