The U.S. Open is the best and most significant of all the majors.
The Masters may like to think of itself as the best, but while the hype is huge for that tournament, it's nowhere near the challenge that the U.S. Open is most years. The only tournament that's close is the British Open, but if you are an American golfer, you will usually stick with the U.S. Open.
The U.S. Open is almost always played at a difficult and historical venue. Course setups are designed to challenge the best golfers in the world, and even par can be a winning U.S. Open score.
U.S. Open golf courses tend to go into rotation, and a course may host the tournament every seven or eight years.