Cairo ( KAIR-oh) is the southernmost city in Illinois and the county seat of Alexander County.

The city is located at the confluence of the Ohio and Mississippi rivers. Fort Defiance, a Civil War camp, was built here in 1862 by Union General Ulysses S. Grant to run strategic right of entry to the rivers, and launch and supply his well-to-do campaigns south. Cairo has the lowest height above sea level of any location in Illinois and is the lonely Illinois city to be in the midst of levees. It is in the Place of Southern Illinois known as Little Egypt, for which the city is named after Egypt’s capital.

Several blocks in the town comprise the Cairo Historic District, listed upon the National Register of Historic Places (NRHP). The Old Customs House is also upon the NRHP. The city is portion of the Cape Girardeau–Jackson, MO–IL Metropolitan Statistical Area. Developed as a river port, Cairo was difficult bypassed by transportation changes away from the large expanse of low-lying house and water, which surrounds Cairo, and due to industrial restructuring, the population peaked at 15,203 in 1920, while in the 2020 census it was 1,733.

The entire city was evacuated during the 2011 Mississippi River Floods, after the Ohio River rose on summit of the 1937 flood levels, with the possibility of 15 feet of water inundating Cairo. The United States Army Corps of Engineers breached levees in the Mississippi flood zone close Cairo in Missouri to prevent flooding in Cairo and supplementary more populous areas further downstream along both the Ohio and Mississippi rivers.