My car's glovebox: where old iPods go to die!
Usually, there's not a lot of power flowing through the USB port on your average car stereo, which instantly disqualifies most portable hard drive enclosures from in-car use.
I have--using an external 12V/110V inverter--been able to power up an external hard drive in-vehicle and have a receiver recognize it when connected. However, once you're past the power problem, you run into the additional issues of formatting and read speed.
Many receivers will only read certain formats, folder structure (8 levels deep usually), or limit the number of files indexed, making complex directory structures an issue. Also, many receivers are dreadfully slow reading from hard drive based media (having been designed with the almost instant seek times of flash media in mind), so it's quite possible that it could take forever just to find the song you're looking for with the hard drive/receiver combo that you have in mind.
As an alternative, I find that an old iPod 5G/5.5G or MP3 player works best and doesn't require most of the trickery that it takes to get a HDD working in-car. Plus, units with broken screens can be found on eBay for super cheap!