This study represents the first attempt to combine the geomorphological characteristics of the island of Ustica with the human settlements that have been established during prehistory, with the purpose of reconstructing the interactions between communities and the natural environment from the Neolithic to the Middle Bronze Age (6th - 1st millennia B.C.). Ustica is a small island in the Southern Tyrrhenian Sea, visible but far (~55 km) from the northern coast of western Sicily. Its rugged volcanic nature, remodeled and enriched by the sea, offered to the first colonizers a wide repertoire of opportunities and challenges. This island can be treated as an ideal “laboratory” to understand how settlers, taking their first steps towards the foundation of organized communities, were able to seize opportunities or succumb to obstacles. The review of archaeological research until now carried out in Ustica, integrated with geomorphological data and other biogeographical indicators, offers a picture of the prehistory of Ustica in which human presence is continuous and distributed in various sites of the island characterized by different physiographic characteristics. There are phases dominated by the choice of naturally protected sites and phases in which settlements expands on open land, suitable for agricultural use. Where the archaeological evidence is scarce, the geomorphological peculiarities allow us to decipher the vocations and characters of a human settlement. The study leads to an open question: in the Middle Bronze Age, after about five thousand years of uninterrupted habitation of Ustica, which factors, geological, social, or other, induced the early communities to abandon the island, without returning there for about eight centuries, until the Hellenistic-Roman age?