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The geological history of the Arabian Peninsula has played a crucial role in shaping current diversity and distribution patterns of many Arabian and African faunal elements. The gecko genus Hemidactylus is not an exception. In this study, we provide an insight into the phylogeny and systematics of 45 recognized species of the so-called Arid clade of the genus Hemidactylus from Arabia, the Horn of Africa, the Levant and Iran. The material comprises 358 specimens sequenced for up to two mitochondrial (12S rRNA, cytochrome b) and four nuclear (mc1r, cmos, rag1, rag2) genes with 4766 bp of the concatenated alignment length. A robust calibrated phylogeny and reconstruction of historical biogeography are inferred. We link the history of this genus with major geological events that occurred in the region within the last 30 million years. Two basal divergences correspond with the break-ups of the Arabian and African landmasses and subsequent separation of Socotra from the Arabian mainland, respectively, segregating the genus by means of vicariance. Formation of the Red Sea led to isolation and subsequent radiation in the Arabian Peninsula, which was followed by multiple independent expansions: 13.1 Ma to Iran; 9.8 Ma to NE Africa; 8.2 to Socotra Archipelago; 7–7.3 Ma two colonizations to the Near East; 5.9 Ma to NE Africa; and 4.1 to Socotra. Moreover, using multiple genetic markers we detected cryptic diversity within the genus, particularly in south-western Arabia and the Ethiopian highlands, and confirmed the existence of at least seven new species in the area. These findings highlight the role of Arabia and the Horn of Africa as an …