In 1548 King Setthathirath (as King of Lanna) had taken Chiang Saen as his capital. Chiang Mai still had powerful factions at court, and the threats from Burma and Ayutthaya were growing. Following the untimely death of his father, King Setthathirath left Lanna leaving his wife as regent. Arriving in Lan Xang, Setthathirath was crowned as King of Lan Xang. The departure emboldened the rival factions at court, who in 1551 crowned Chao Mekuti as king of Lanna.^[36] In 1553 King Setthathirath sent an army to retake Lanna but was defeated. Again in 1555 King Setthathirath sent an army to retake Lanna at the command of Sen Soulintha, and managed to take Chiang Saen. In 1556 Burma, under King Bayinnaung invaded Lanna. King Mekuti of Lanna surrendered Chiang Mai without a fight, but was reinstated as a Burmese vassal under military occupation.^[37]

In 1560, King Setthathirath formally moved the capital of Lan Xang from Luang Prabang to Vientiane, which would remain the capital over the next two hundred and fifty years.^[38] The formal movement of the capital followed an expansive building program which included strengthening city defenses, the construction of a massive formal palace and the Haw Phra Kaew to house the Emerald Buddha, and major renovations to That Luang in Vientiane.

The Burmese turned north to depose King Mekuti of Lanna, who had failed to support the Burmese invasion of Ayutthaya in 1563. When Chiang Mai fell to the Burmese, a number of refugees fled to Vientiane and Lan Xang. King Setthathirath, realizing that Vientiane could not be held against a prolonged siege, ordered the city to be evacuated and stripped of supplies. When the Burmese took Vientiane they were forced into the countryside for supplies, where King Setthathirath had organized guerrilla attacks and small raids to harass the Burmese troops. Facing disease, malnutrition and demoralizing guerrilla warfare, King Bayinnaung was forced to retreat in 1565 leaving Lan Xang the only remaining independent Tai kingdom.^[39]