I think the biggest single mistake I see people making with a GPS is setting it for the "Shortest Route". In some areas, that route will have you following the cows to the barn over an unmaintained back road. Setting it to the "Fastest Route" will usually keep you on better roads, albeit a bit longer ones. Having a pretty good idea of what the road conditions on your route should be though, whether from paper maps, online maps, or satellite views, is always a good idea of course, so you know pretty quickly when something goes awry.