The two largest cities in Latgale are Daugavpils and Rezekne.

Daugavpils, with a population of 120,000, is the largest city in Latgale. Its historic importance comes form its location on the Daugava as a crossroads on the ancient river route form the Baltic to the Black sea and as a central point on the rail route between Warsaw and Moscow and Warsaw to St. Petersburg. Its historic names include Dunaburg and Dvinsk. It has always had a large number of foreign residents. In the interwar period Daugavpils (Dvinsk) was a vibrant center of Jewish culture and activity. Presently it is an industrial city with a variety of industries including textile, locomotive repair, machine factories and other plants. In the Soviet period the city became heavily russified. Presently the Lavian population of Daugavpils is only about 13% but the Latvian life the city is being revived. The remainder of the population is composed of Russian, Polish, Belorussian and other ethnic groups.

Rezekne, the next largest city, is known as "The Heart of Latgale". It is an historic city which has ancient castle ruins in the center of the city. It has a population of 42,900. It is the cultural center of Latgale and has been the center of Latgalian political life. In 1917 it was the site of the historic Congress, which called for Latgale's unification with the rest of Latvia. Its street names honor the leading figures in Latgalian history. One of the main sites is the statue of the Latgalian maiden "Latgales Mara" honoring the liberation of Latgale. Demolished by the Soviets it was restored in 1992. Rezekne has a University, an Art School and the Latgalian Cultural Museum. Nearby are Lake Rezna and other lakes in a very picturesque countryside. Presently it has a population of 42,900. Other important cities in Latgale are Preili, Ludza, and Vilani.

Livani was founded in 1533 by the Lieven family. They selected the site because it was on the water route from Daugavpils to the Dubna river network. But the town passed into the hands of other families and in the 19th century was owned by Baron Koris. In 1904 a glass factory was established in the city. Soon Livani became famous for its glass and crystal.

Preili is important because of its role as the political center of the region in the 20th century. Its historic background dates to the fourteenth century. In 1382 it had become a possession of the famous Borch family. Beginning in 1472 it had become the residence of Nernd fon den Borch, the head of the Livonian Order. By the mid-19th century Preili had grown into a trading and commerce hub. Its population included many merchants. Also Preili had a large Jewish population. In the 20th century Preili became the administrative center of the Preili County. It is famous for its ceramics and is the home of Polikarps Cernavskis, the famous ceramist.

Ludza is an ancient town. Its founding dates back to 1177. There was an ancient settlement of the Latgali as early as the 10th century. The Teutonic Order captured it in 1399. The Latvians and the Russians fought for control of it for several centuries. In the 19th century it became a thriving commercial town until the advent of the Moscow-Rininskas railway. In independent Latvia Ludza became the capital of the Ludza district.