Interstate 255 (I-255) is a bypass route of Interstate 55 near St. Louis, Missouri and with Interstate 270, it forms a loop around the city. Even though St. Louis is in Missouri, a majority of the route runs through Illinois. It shares its southern terminus with 270 at the junction with Interstate 55, 270 goes to the west and 255 goes to the east. US 50 joins I-255 at Lemay Ferry Road. It crosses the Mississippi River on the Jefferson Barracks Bridge, enters Illinois, and then turns north. There is a junction with Interstate 64, where US-50 breaks off and goes east, and then further north there is a junction with Interstate 55 again, Interstate 70, and U.S. Route 40, all of which are all co-signed together. The next junction is another one with Interstate 270, and it is the northern terminus of Interstate 255. After that, it becomes Illinois Route 255.

Interstate 255 is 30.82 miles (49.60 km) in length.

I-255 route was proposed from I-55/I-244 near Green Park to I-55/70 west of Cahokia Mounds near the intersection with IL 111 when plans surfaced in the 1950s Yellow Book. It was originally supposed to be a 4 lane highway but was changed to six lanes.

Since that routing was to go through the American Bottoms, archaeological investigations had to be conducted prior to any constructions, which would later become known as the FAI 270 Series. When Cahokia Mounds was designated in the federal register, a new alignment for I-255 from I-64 to I-55/70 had to be picked.

As a result, this was the last interstate highway in the St. Louis area to be built as construction did not start until the late 1970s. During this time, the entire interstate loop would become I-270. However, the state of Illinois would start making their supplemental freeway plans during this time period and this included a routing from I-55/70 to I-270 in Madison County that would become "Corridor 413".

In 1978, the southern most 6 mile section of Corridor 413 would be added to the Interstate Highway System. This change caused a potential place of confusion where two intersecting highways would have the same number, and IDOT started floating with the I-270/870 routing for the east-west leg in Madison County. The locals did not care for that numbering alternative, as both the Alton Telegraph and Edwardsville Intelligencer was still referring that new highway as I-255 in various articles. In addition, the portion of the Corridor 413 from I-270 to US 67 (then IL 267) was heavily hyped by the local politicians as several nearby highways were already congested by that point of time. By 1980, IDOT decided on the 255 numbering.

I-255 leaves I-55 and I-270 as a east/west highway. This section to the JB Bridge was built in the 1960s and upgraded between 2002-2004 with new pavement and the replacement of the Telegraph Road bridge. Past Koch Road, I-255 crosses the Mississippi River on the Jefferson Barracks Bridge, known to the locals as the JB Bridge. Past this point, this highway is now signed as a north/south highway, and appears considerably newer than the Missouri section. The section from the JB Bridge to I-64 was opened to traffic between 1984 to 1985.

At the IL 3 interchange, I-255 makes a sharp turn north and is briefly duplexed with IL 3 in the Dupo area. When IL 3 splits, I-255 takes more of a northeast turn through the eastern side of Cahokia and East St. Louis. The Mousette Lane interchange was completed in the 1990s and is now the site of the Gateway Grizzlies baseball along with a business park located next to St. Louis Parks Airport. This section of 255 features shorter light poles to accommodate planes taking off and landing on the nearby airstrip. As a result, some of the best views of the St. Louis skyline can be observed in this area.

North of there, 255 continues through a portion of Frank Holten State Park before meeting up with I-64 just west of Caseyville. The section of 255 from 64 to 55/70 was opened on October 23, 1986, and it has a further east alignment than originally planned. 255 will cross Black Lane and two railroad tracks on a massive viaduct then intersect Collinsville Road just east of Fairmont Park racetrack.

255 will then intersect 55/70 and change its control cities from "Chicago" to "To I-270". The section from 55/70 to 270 was opened on July 26, 1988 and was not part of the original plans. (It was actually part of the plans that eventually became Illinois 255 that the politicians in the Alton-Wood River area started dreaming back in the 1970s.)