Margaret was twice widowed by the age of twenty-six. Her father Maximilian I made her regent of the Netherlands in 1507 and she ran the territory until her death in 1530, conducting diplomacy with Henry VIII, Francis I, and the Pope through a network of agents based out of Mechelen. Her residence, the Hof van Savoye, was one of the first true Renaissance buildings north of the Alps, completed in 1517 by Italian craftsmen. She raised four nieces and her nephew Charles within its walls. Anne Boleyn, the future queen of England, spent a year at Margaret's court as a young attendant before being sent on to France. The composers Pierre de la Rue and Josquin des Prez wrote masses for the regent's chapel. When the political center moved to Brussels in 1530 the building was eventually converted into law courts, which it remains.

St. Rumbold's Cathedral was begun shortly after 1200 and consecrated in 1312, but the tower that dominates the modern skyline was a fifteenth-century afterthought. The original plan called for 167 meters, which would have made it the tallest church tower ever built, taller than the Ulm Minster. The Keldermans family of master masons started construction in 1452. They built ninety-seven meters of solid masonry and then, in 1520, ran out of money. A seventy-seven-meter spire was supposed to top it; only seven meters of that were finished. The result is the strange flat-topped silhouette you see today, a UNESCO World Heritage Site as part of the Belfries of Belgium and France. Pope John Paul II climbed the 514 steps on his sixty-fifth birthday in 1985 and reportedly told the city carillonneur: your tower is not complete.

When the political importance went away, the manufacturing stayed. Mechlin lace, a precise bobbin lace with hexagonal mesh, became internationally famous in the eighteenth century; Marie Antoinette ordered it by the yard. The De Wit manufactory, housed since the 1980s in the Refuge of Tongerlo abbey, restores fine sixteenth-century Flemish tapestries for museums around the world; it is one of the only operations in Europe still capable of the work. The furniture-making tradition that began in the rebuilding after the Spanish Fury of 1572 is still active. So is Het Anker, one of the oldest breweries in Belgium, which produces a beer called Mechelsen Bruynen that was, by tradition, the favorite of Charles V. Vegetables matter here too: the Mechelse Veilingen co-operative in nearby Sint-Katelijne-Waver is the largest produce auction in Europe.

On the Dijle quay opposite the historic center stands an eighteenth-century barracks built by Maria Theresa of Austria. Between 1942 and 1944 the SS used it as the assembly point for the deportation of Jews and Roma from Belgium. Twenty-eight trains left from the small siding behind the barracks, carrying 25,490 Jews and 353 Roma to Auschwitz. About 1,200 returned. The building is now the Kazerne Dossin, the Jewish Museum of Deportation and Resistance, opened in its current form in 2012. The exhibition does not soften what happened. It names the people who left, photograph by photograph, an entire wall of faces. Most of them were Antwerp residents, brought south by the SS because Mechelen had good rail connections to the east. The barracks were chosen for the same reason the Belgian railway hub developed here in 1835: the trains went everywhere from this point.