The first European to "discover" the site of Pittsburgh was French discoverer/trader Sieur de La Salle in his 1669 expedition. The settlement of Pittsburgh began as a strategic point at the confluence of three rivers, with Britain, France, and the local Native American tribes all vying for control over this spot and thus, the region. On what is now referred to as The Point, where the rivers meet, several forts were constructed by competing French and British forces during the French and Indian War. In 1758, British general John Forbes ordered the construction of Fort Pitt, named after British Secretary of State William Pitt the Elder. He also named the settlement between the rivers "Pittsborough".

Manufacturing in Pittsburgh began in earnest in the early 19th century, and by the US Civil War the city was known as "the armory of the Union." This began a sharp escalation of industry, particularly steel and glass. By the late 19th century, Pittsburgh was known as the Steel City. Andrew Carnegie began the Carnegie Steel Company in 1892, which became United States Steel (USS) a decade later and grew to be the largest corporation of any kind in the world. Carnegie became the richest man on Earth and, along with other local magnates of industry, gave Pittsburgh cultural institutions such as the Carnegie Museums, Carnegie Library, and Carnegie-Mellon University. A number of other Fortune 100 companies have called Pittsburgh their headquarters, helping fund world-class museums, theaters, universities, and other attractions.

At the height of this industrialization Pittsburgh was notorious for its severe air pollution. One journalist, James Parton, descriptively dubbed it "hell with the lid off". White-collar workers came home in the evening as "brown-collar" workers. When asked what to do to fix Pittsburgh, the noted architect Frank Lloyd Wright famously replied with his characteristic frankness, "Raze it." Following World War II, the city launched a clean air and civic revitalization project known as the "Renaissance." This much-acclaimed effort was followed by the "Renaissance II" project, begun in 1977 and focusing more on cultural and neighborhood development than its predecessor. The industrial base continued to expand through the 1960s, but beginning in the 1970s and 1980s, the steel industry in the region imploded, with massive layoffs and mill closures.

Today Pittsburgh is a model of cleanliness due to the remediation of the polluting industrial plants in the late 1950s, as well as the gradual migration of the mills to other cities and countries. There is now only one operating steel mill in the region, Carnegie Steel's venerable Edgar Thompson Works, now a USS state-of-the-art integrated steel mill. With the implosion of the steel industry in the region, the city's population shrank dramatically, from 600,000 in 1950 to 330,000 in 2000. Remnants of the city's more prosperous past can be seen throughout the area. But while the region is still reeling from the economic collapse, Pittsburgh is now (for the most part) economically stable, as the city has shifted the economic base to services such as education, medicine, technology, and finance.