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Due to the wide influence of Italian and Greek immigrants in American culture, the United States has developed quite a large number of regional forms of pizza, many bearing only a casual resemblance to the Italian original. During the latter half of the 20th century, pizza in the United States became an iconic dish of considerable popularity, and may have contributed to the decline of the British pie heritage previously common in American cuisine.

The most Americanized style of pizza is the classic pepperoni pizza. It is made with classic pizza dough and marinara sauce, topped with mozzarella and cheddar cheese. A layer of pepperoni is then applied and the pizza is then cooked. The thickness of the crust depends on what the consumer prefers; many people consume pepperoni pizza with thick and thin crust. New York-style pizza is a style originally developed in New York City, where pizza is often sold in oversized, thin and flexible slices. It is traditionally hand-tossed, moderate on sauce, and moderately covered with cheese essentially amounting to a much larger version of the Neapolitan style. The slices are sometimes eaten folded in half, or even stacked, as its size and flexibility may otherwise make it unwieldy to eat by hand. This style of pizza tends to dominate the Northeastern states and is very similar to the basic style common through the United States and known simply as pizza. It is often referred to as pan-style pizza, but note that Pizza Hut's "Pan Pizza" is a thick-crust variety. Many pizza establishments in the New York metropolitan area offer two varieties of pizza: "Neapolitan", or "regular", made with a relatively thin, circular crust and served in wedge-shaped slices, and "Sicilian", or "square", made with a thicker, rectangular crust and served in large, rectangular slices. Chicago-style pizza, or Chicago-style deep dish pizza, contains a crust which is formed up the sides of a deep-dish pan. It reverses the order of ingredients, using crust, cheese, filling, then sauce on top. Some versions (usually referred to as "stuffed") have two layers of crust with the sauce on top. Deep-dish pizza was purportedly invented and first served in 1943 at Pizzeria Uno, which is still operating along with its twin restaurant, Pizzeria Due, in the River North neighborhood.

Chicago-style thin crust pizza has a thinner crust than Chicago-style deep dish, and is baked flat rather than in a deep dish pan. The crust is thin and firm enough to have a noticeable crunch, unlike a New York-style pizza, yet thick enough to be soft and doughy on the top. The crust is invariably topped with a liberal quantity of southern-Italian style tomato sauce, which is usually quite herbal or highly spiced, and typically contains no visible chunks of tomato. Next, a layer of toppings is added, and a layer of mozzarella cheese which frequently separates from the bottom crust due to the quantity of tomato sauce. Chicago-style thin crust pizzas are cut into three- or four-inch squares, also known as "party cut," as opposed to a "pie cut" into wedges. The small size of the squares makes it unnecessary to fold the slices. Chicago-style pizza is prevalent throughout the Midwestern USA. Chains that are well known for Chicago-style thin crust pizza are Home Run Inn and Old Chicago.