During the mission-planning phase, make sure to plot the waypoints for your ingress and egress routes around enemy antiaircraft concentrations. Although it may take longer for the bomber fleet to reach its objective(s), the formation won't have to fly through as much flak, which will hopefully cut losses and make your bombing run that much more effective.
Don't forget that in addition to the bombers, you can take over the controls of your fighter escorts at any time during play. Consider hopping in the fighter escorts during the early phases of the mission to keep the enemy fighter opposition at bay as long as possible. You can always switch back to the bombers whenever the enemy fighters are within attack range of the bomb group.
If you're playing the bomber campaign, don't bother going after distant targets such as Berlin until the spring of 1944, when long-range P51D Mustangs are available to escort the bomb group to and from the target.