I wouldn't say it's particularly difficult (although it's not as good as driving in the US) - It really depends where in Spain, and the quality of the road network you are staying.
I've driven in mainland Spain twice which was great, Ibiza and Majorca dozens of times - they are just OK, Lanzarote wasn't too good at all.
Just don't get too cocky, expect to have horns beeped at you - and when entering large towns try and slow down a bit and look out for stupid tanked up pedestrian tourists who don't know which way to look. Also make sure you understand what type of fuel to put in the car, and how to pay for it at the petrol station (as some require you to pay before hand) - Always keep your licence, documents etc with you and make sure you know the number of the hire firm in case of problems.
Always pay most attention when first taking off after getting into the car. You may find you automatically go onto the wrong side of the road into the path of another car. Not good - but it won't take long for your brain to switch to the other side of the road and work out the new passing widths etc.
Another thing you definately don't want to do is leave anything remotely valuable in the car when you leave it - as car crime is terrible in most of spain.