The default loadout for each aircraft is a passenger in every seat and fully loaded baggage compartments. Kick some of this dead weight out to make your plane lighter and more responsive, and to get more mileage from your fuel.
Tune your radio
Open the Vector Map (Shift-M) to get an overhead view of your position. Click on airports and navaids to bring up their info boxes, then click on the radio frequencies in the box to automatically tune your radio.
Navigation
To learn the art of navigation without relying on GPS, start with a short flight between two nearby airports and concentrate on learning the VOR and DME equipment. Then plan longer flights with multiple waypoints.
ATIS
Be sure to contact ATIS (Automatic Terminal Information Services) at the airport from which you're taking off to file your flight plan and start the chain of air traffic control steps that will guide you to your destination.
Patch
Download the latest patch from Gathering of Developers' Web site; Fly shipped with some pretty egregious bugs that are in the process of being tidied up.
