At its southern end, Wilhelmstraße originally met with Friedrichstraße, which runs roughly parallel to the east, on the Belle-Alliance circus, before the street course was westerly redirected to the Stresemannstraße junction about 1970.

In 1731 the Husarenstraße (Street of the Hussars) was built as a north-south thoroughfare of the Baroque city layout, where many Huguenots, who had fled from France, as well as expelled members of the Moravian Church settled.

Several personal confidants of the king had large city palaces erected, most notably General Kurt Christoph Graf von Schwerin and the French Baron François Mathieu Vernezobre de Laurieux, who took his residence in the later Prinz-Albrecht-Palais.

Originally a wealthy residential street, with a number of palaces belonging to members of the Hohenzollern royal family, the Wilhelmstrasse developed as a Prussian government precinct from the mid 19th century.

This building now called Palace of the Reich President housed an administrative seat of the Prussian minister for the Royal Household, from 1861 led by Alexander von Schleinitz.

After World War I the Palais Schwerin was sold by exiled Emperor Wilhelm II to the Weimar Republic government and in 1919 became the residence of the first Reich President of Germany, Friedrich Ebert.

Until the death of his successor Paul von Hindenburg in 1934, the President's official residence was at Wilhelmstraße 73, where he could watch the torchlight parade on the night of the Nazi Machtergreifung on 30 January 1933, after he had sworn in Adolf Hitler as German chancellor.

This building, a prime example of Nazi architecture, stood immediately south of the old Chancellery, on the corner of the Wilhelmstrasse and the Voss Strasse, and its official address was Voßstraße 4.

The Foreign Office moved into the former Reich President's palace, the old building being refurbished in grandiose style at the behest of Nazi Minister Joachim von Ribbentrop.

In 1935/36 his party fellow Hermann Göring had the huge Ministry of Aviation edifice designed by Ernst Sagebiel built on the corner with Leipziger Strasse.

The adjacent Prinz-Albrecht-Palais in the south became notorious as the seat of the Sicherheitsdienst of the Reichsführer-SS and the Sicherheitspolizei chief-of-staff; merged into the SS-Reichssicherheitshauptamt terror complex under Reinhard Heydrich in 1939.

Other public institutions on Wilhelmstraße include the ARD-Hauptstadtstudio (television studio) of the ARD broadcasting organization at the northern Spree riverside, the E-Werk techno club, the Topography of Terror museum at the former Reichssicherheitshauptamt site, and the Willy-Brandt-Haus headquarters of the Social Democratic Party of Germany on the southern corner with Stresemannstrasse.