Quick answer
¿Cuánto cuesta?
the everyday version
¿Cuánto es?
the alternative — see below for when
Which one to use
Use ¿Cuánto cuesta? when pointing at one product: it literally asks what that thing costs.
Use ¿Cuánto es? at the till, when you want the whole bill. For several items, the plural ¿Cuánto cuestan? is the correct form.
All the versions
¿Cuánto cuesta?How much does it cost? — one item.
¿Cuánto cuestan?How much do they cost? — several items.
¿Cuánto es?How much is it altogether? — at the till.
¿Cuánto vale?What’s it worth? — very common in Spain.
La cuenta, por favor.The bill, please — in a restaurant.
Where you are matters
<b>¿Cuánto vale?</b> is typical of Spain, while <b>¿Cuánto cuesta?</b> is the safest choice anywhere in Latin America.
Check yourself
You are at the checkout paying for everything together. What do you ask?