So you've never been to Spain...
...where do you start?
Spain is overwhelmingly rich in historic sites, having preserved quite well buildings/ruins/sites going as far back as the Romans and even before them.
Having said that, you will find everywhere a good mix of well maintained Roman, Jewish, Moorish, and Christian sites. It is purely amazing and you will need probably years to visit everything Spain has got to offer.
A good way to go about this is to divide and conquer - focus on the big cities, for example - Madrid, Barcelona, Seville, Bilbao, etc. Or take the Roman's Route for example. Or go for the Way of Saint James - which is a good way to revisit famed Christian sites and pilgrimage attractions. Visit the birth place of conquistadores in Trujillo. Or the castles spread all around the country.
It also depends on how much time you have. If you have less than a week and you have never been to Spain, focus on the big cities, and travel by fast train. If you have 10-14 days, it is worth picking a theme and renting a car to see everything at your own pace (see below my suggestions).
A good way to start is by reading the guides offered by http://www.frommers.com, http://www.lonelyplanet.com, etc. They are usually rather good at giving you a snapshot of everything Spain has to offer, although the amount of information can be a bit overwhelming.
Also try http://www.spain.info - the official Spain tourism website.
For prepackaged suggestions, go to the Spain page and look for the following themed-packages (they all get you to drive, which I think it's a better option if you have the luxury of time):
Northern Spain and the Green Coast;
Magic Triangle
The Way of Saint James;
Dreamy Andalucia;
Or for quick train packages - try any of the following combinations: Madrid - Seville - Cordoba - Granada - Barcelona, etc.
My personal experience: a 10 day trip including Madrid, Cordoba, Seville, Merida, Trujillo, Caceres, Salamanca, Medina del Campo, Coca, Segovia, La Granja de San Ildefonso, Avila, and Toledo - which included a good mix of Roman, Moorish, Jewish, and Christian heritage. We also visited many castles and many past and present cultural centers (such as Salamanca). Trujillo was certainly impressive and we took the obligatory shot with Pizzaro.