In 1927, facing a Post Office deadline for the commencement of mail carriage, Pan Am had no working equipment for its sole airmail contract between Key West and Havana. Fortunately for Pan Am, a pilot with his Fairchild seaplane arrived at Key West and was willing to carry the mail to Cuba for the start up operation. It is fitting that Pan Am's first flight would be over water, since the airline would pioneer overseas routes throughout its history.

Pan Am's fortunes took a turn for the better in the fall of 1927. Through the heavy lobbying efforts of Juan Trippe, Pan Am was selected by the United States government to be its "chosen instrument" for overseas operations. Pan Am would enjoy a near monopoly on international routes. Added to Pan Am's Cuba route were lines serving Mexico, Central America, the Dominican Republic, Haiti and Puerto Rico. Most of these destinations were port cities, which could be reached only by landing on water. Therefore Pan Am made good use of its "flying boats," the Sikorsky S-38 and S-40. Flights were eventually expanded to serve much of South America as well.

Pan Am’s fleet of Clippers allowed the airline to conquer the Pacific in the mid-1930s. The flying boats would later be put to military use in WWII.

Just a few years later, Pan Am launched its effort to cross the world's largest oceans. Survey flights across the Pacific were conducted with the Sikorsky S-42 in 1935, but passenger service required bigger and better aircraft. Accompanied by much fanfare, the Martin M-130 was introduced in 1936, followed by the Boeing 314 in 1939. Known as Pan Am Clippers, these mammoth flying boats flew from San Francisco harbor skipping across the Pacific with stops at Hawaii, Midway Island, Wake Island, Guam, the Philippines and then Hong Kong. Advance teams had prepared the stopover islands by blasting coral to make safe coves for sea landings and constructing luxury hotels for Pan Am's discerning, rich clientele. Next on the Pan Am list for conquest was the world's other major ocean - the Atlantic. The Boeing 314 entered European service in 1939 flying from New York to Lisbon and Marseille by way of the Azores.

World War II slowed passenger service but not Pan Am operations. Pan Am flew over ninety million miles on behalf of the war effort. Pan Am's international route system would benefit greatly by the wartime construction of airfields at locations around the world. These airports were converted to passenger use after the war's conclusion. The era of the flying boat was over, but the era of the jet was about to begin.

Pan Am was the first U.S. airline to begin commercial jet service when they began flying Boeing 707s in 1958.

The post-war years saw huge growth in tourist travel. Pan Am met demand by being the first to introduce the newest planes. In the early 1950s, Pan Am added to its fleet classic airliners like the Lockheed Constellation and Boeing Stratocruiser. But Pan Am forced the entire industry to take a giant leap ahead when it was the first airline to begin passenger jet service. At a time when there was little enthusiasm for the jet airliner, Pan Am's Juan Trippe managed to play Boeing and Douglas Aircraft off each to convince both to produce jets for an unknown market. Pan Am added both the Boeing 707 and the Douglas DC-8 to its fleet. In 1958, Pan Am inaugurated jet service with flights from New York to Paris. Flying time was cut in half. Comfort and smoothness of flight were increased immeasurably. To remain competitive, the other airlines found it necessary to enter the jet age whether they wanted to or not.

In the 1960s, Juan Trippe saw need for a high-capacity, long haul aircraft to keep pace with the forecasted increase in air travel. The plane was the Boeing 747. Introduced in 1969, the 747 arrived at an unfortunate moment for Pan Am. A sharp downturn in air travel caused major financial difficulties for the airline. The purchase of the 747 fleet was a major cause of Pan Am's steady decline over the next two decades.

To make matters worse, the governmental favors enjoyed by Pan Am for years gave way to increased hostility against the airline for its monopolistic ways. International routes were granted to Pan Am's rival airlines, while Pan Am was barred from starting its own domestic operations. When deregulation allowed Pan Am to enter the domestic market, it jumped at the opportunity by acquiring National Airlines in 1980. But the integration of the two airlines' routes and equipment was less than seamless. Debt continued to mount. Just to stay in the air, Pan Am was forced to liquidate assets. Most shocking was the sale in 1985 of its entire Pacific Ocean network to United Airlines. Soon thereafter, Pan Am sold its New York - London route. In 1991, Pan Am was forced to declare Chapter 11 bankruptcy. After a few months of flying in a joint venture with Delta, Pan Am went under in December of 1991. The airline name was purchased out of bankruptcy court and now offers limited service between just a few cities.