There once were four direct railway routes between Liverpool and Manchester in North West England; only two remain: the centre routes of the four. The most northerly and the most southerly of the four routes are no longer direct lines. Of the remaining two direct routes, the northern route of the two is fully electric, while the now southern route is mostly a diesel-only line, with only the westernmost section shared with the West Coast Main Line being electrified. The most northerly of the four has been split into two routes: the western section operated by Merseyrail electric trains and the eastern section by diesel trains, requiring passengers to change trains between the two cities. The fourth route, the most southerly of the four, has been largely abandoned east of Warrington; the remaining section caters mainly for freight trains.

The remaining two direct routes are:

The northern route runs from Liverpool Lime Street, via Earlestown and Newton-le-Willows, and continues to either Manchester Victoria or Manchester Piccadilly. The line follows George Stephenson's original 32-mile (51.5 km) Liverpool and Manchester Railway of 1830, which was the world's first inter-city passenger railway and the first to have run 'scheduled' services. Many early steam locomotives were initially used on this line including Stephenson's Rocket, which won the Rainhill Trials in 1829 (see List of Liverpool and Manchester Railway locomotives). The line also includes listed structures including stations and bridges, particularly the Rainhill Skew Bridge and the nine-arch Sankey Viaduct.

Following completion of electrification in May 2015, services to Manchester Airport and Manchester Victoria are operated by Class 323 three-car and Class 331 three-car and four-car electric multiple units (EMUs).

Northern Trains operates two trains per hour on the Chat Moss line, an hourly all-stops service from Liverpool Lime Street to Manchester Airport operated by Class 323 and 331 EMUs and an hourly service from Chester to Leeds via Bradford Interchange which calls at Earlestown and Newton-le-Willows, operated by Class 195 diesel multiple units (DMUs).

During weekday peak times, two daily return trains operate between Liverpool Lime Street and Manchester Victoria: one service in the morning and one in the evening, calling at all stations. Six daily return trains also operate between Manchester Victoria and Wigan North Western: three services in the morning and three in the evening at hourly frequency via Eccles, although only morning services towards Manchester and evening services towards Wigan call at the station.

A limited service operates between Ellesmere Port and Liverpool via the western section of the Chat Moss route, calling at all stations between Earlestown and Lime Street.

Between Earlestown and Manchester Airport, there are additional hourly services operated by Transport for Wales, which originate from Llandudno via the North Wales Coast Line and Chester.