The desert is nearly impassable. Obviously it’s plagued by some giant sandworm-like creatures, as well as its environmental hazards. Surely someone crosses it, though! You have desert caravans in your D&D world, right?
Whoever the caravan masters are – humans? halflings? dragonborn in 4e? – they need some way to fight off the sandworms, blue dragons, and other high-level desert creatures. With food and water so scarce, there’s no way that hundreds of defenseless creatures – walking meals – are going to make it alive across the wastes, even if they do make a practice of hiring PCs as guards.
Since D&D is a post-apocalyptic game, the caravanners may well have cobbled together a Jawa sandcrawler-type vehicle from the magical vehicles of previous ages. It’s all Mad Max scrap metal, giant tank treads and armor, but seamed with golden light and bolted with runes. The desert crawler must be armed with a weapon powerful enough to keep the giant monsters at bay. Solar power is the traditional technology of all-knowing progenitor cultures, so let’s give it a mirror cannon that focuses beams of radiant energy.
No magic engine has survived from the ancient empires, so the desert crawler is powered by slaves in treadmills. The slaves are mostly the orcs and elves who live on the desert’s border. The caravan is always looking to buy strong slaves, so if the PCs are defeated in the desert by any intelligent opponent, they may wake up in a treadmill themselves.
How do the PCs escape from the caravan? Straying from the caravan’s oasis-dotted route invites death from thirst and sandstorm. Falling behind will put the escapees in the midst of the swarm of landsharks who pick off stragglers. Traveling ahead? Possible, but only the caravan leader has a map of the route.
The best option is the classic swashbuckling approach: free the galley slaves, throw the slavers to the sharks, and become a privateer on the desert sea.