One of the original roles of the B-17 was as continental defense: with its long range, speed, ceiling, and bombload, it was intended to clobber ships way out at sea. As we know from OTL combat experience, the inaccuracy of bombing from altitude, plus the ability of ships to maneuver away in the time it took for the bomb to fall, made high altitude bombers ineffective in this role.
What if the US had realized this shortly after the B-17 had entered service and elected to solve the problems of high altitude level bombing by developing guided munitions? The OTL US followed several guided bomb programs later on in the war - a rocket-boosted bomb guided by radio control, a bomb with a TV camera in its nose, and an infrared-seeking bomb.
What consequences follow from high altitude bombers actually being able to hit what they're aiming at - even if it's maneuvering? Does Midway get even worse for the IJN if the 15 B-17's coming off Midway are able to hit ships during their raid? What kind of effects does it have on German industry if bombing raids are that much more efficient?