Most places still won't take American Express, so it will be good to stick with Visa or Mastercard. And - I don't know if this has changed at all - we once used our credit cards - instead of our debit cards - to withdraw cash from an ATM in Europe. Big mistake! We didn't know it but the bank started charging interest right away on our "loan", and we received a large credit card bill later that month. We vowed never to do that again.
Also, in Spain, if you use your credit card at a vendor (store, restaurant, etc) they will ask you if it's PIN or "firma" (signature). If your card doesn't have a PIN, you'll say "firma" and then they'll ask to see your ID (passport should be fine). They are very consistent about checking your ID here, so you can be prepared for that.
Buen Camino!