Lesbos (also known as Mytilene) is the third largest island in the Aegean archipelago. Rich in natural resources, it lies at a key geographical location near the Hellespont and the Asia Minor coast. From early antiquity onwards it developed its own distinct culture, making a decisive contribution to the diverse mosaic of Aegean culture.

Signs of human life dating to as early as the Neolithic period have been found on the island, while continuous habitation began in the 9th century BC. Lesbos was influenced by the transfer of the capital of the Roman Empire from Rome to Constantinople in the 4th century AD, and the spread of Christianity, as it is close to both Constantinople and the major centers of the East. It seems that the new religion was introduced to the island by St. Paul the Apostle, when he visited in 52 AD, though sources are unclear as to when Christianity spread to Lesbos. What is certain is that by the first quarter of the fourth century Mytilene was organized into a diocese, as in 325 its bishop, Gregory, is mentioned as taking part in the First Ecumenical Council at Nicaea in Bithynia. At the beginning of the sixth century it would appear that Mithymna also acquired a diocese. The economic prosperity of the first Christian centuries is evidenced by the remains of private homes on the island, such as the so-called House of Menander, a luxurious 4^th century residence decorated with mosaics , and by the remains of communal and public buildings, such as the magnificent bath house and the large domed public building with mosaic floors in the town of Mytilene.

Many basilicas dating to the early Christian Period have been located throughout the island, the most notable being the churches of St. Demetrius Ypselometopou, St. Andrew and Afentelli in Eresos, the basilicas at Loutra, Chalinados and Achladeri (the largest of the early Christian monuments in terms of area so far excavated). Mosaics unearthed in various parts of the modern city of Mytilene and the harbor area belong to churches of that time. The continuity of tradition in mosaic making is evident; similarity between works is not restricted to construction techniques, but extends to decorative motifs that are repeated unaltered, exhibiting a fine sense of color and design. Furthermore, in the reign of Justinian construction work began on the castle at Mithymna and the city of Mytilene.
During the 7th and 8th centuries Lesbos was plagued by Arab invasions that resulted in a dwindling population and a significant economic downturn. Building activity ground to a halt, thus accounting for the lack of monuments from the period.  During the 9th century, despite repeated Saracen and Russians raids, Lesbos seems to have recovered. Up until the 11^th century the island was to serve as a place of exile for prominent persons, including Constantine IX Monomachus before he was crowned emperor.

During the late 11th century Lesbos was once again thrown into turmoil, raided twice by Jahan the Turk, who managed to occupy the entire island with the exception of Mithymna. Byzantine intervention under Constantine Dalassenus and John Ducas eventually proved successful in retaking the island. It would appear that during this period Alexius I Comnenus carried out repair works on the castle of Mytilene. From 1128 to 1204 the role of prospective conqueror passed to the Venetians, who carried out repeated raids. After the empire was overthrown by the Franks, Lesbos fell to the Western Roman Emperor, but in 1261 it was reincorporated in the Byzantine state following the recapture of Constantinople by Michael VIII Palaeologus .

Earlier that year (1261) Michael VIII Palaeologus and the Genoese signed the Treaty of Nymphaeum, by which the two forces managed to oust the Venetians from the Aegean. In return, the Genoese were granted exclusive control over many island ports and free trade privileges in all other imperial ports. It was then that the first Genoese trading community was established in Lesbos. In 1335 the entire island was captured by the Genoese Domenico Cattaneo, who had previously been based in New Phocaea. Efforts by Byzantine Emperor Andronicus III Palaeologus to force Cattaneo from the island resulted one year later in capitulation between the two powers, with the Genoese remaining in Lesbos on condition that tribute was paid to the Byzantine state.

A new phase in Genoese rule on Lesbos began a few years later, in 1355. In return for assistance rendered to Emperor John V Palaeologus in regaining the Byzantine throne, Genoese merchant Francesco I Gattilusio was married to the emperor’s sister, Maria Palaeologus, and received the island as dowry. One of the first projects Gattilusio undertook was to rebuild and reinforce the castle of Mytilene. Yet a violent earthquake in 1384 not only caused serious damage to the castle, but also struck the family of Francis and Mary Palaeologus, as only their youngest son survived the earthquake. The Gattilusi period on Lesbos came to an end in 1462, when the island was surrendered to the Ottomans under Mehmet II.