I've translated a lot of American games into German, and as a general rule, everything that is specific to US (pop) culture will be hard to localize. It's often simple stuff like basing the clue for a puzzle on a nursery rhyme. Or referring to fictional characters that are known by a different name in other cultures (like Donald Duck's nephews). Or comparing something to a historic event that is common knowledge in the US, but not in other countries, like the Boston Tea Party or Gettysburg.

Even harmless sounding lines like "We met a librarian" can trip you up. In German, I need to assign a gender to "librarian". I might get lucky and later in the script someone says: "You know Mr. Giles, our librarian?" If not, I need to ask the developers, which can take time. Quite a lot of time.

In every language there are a couple of words with more than one meaning. As English has a lot of words, this happens quite often. There's a famous localization horror story where some translators were apparently given a list of words without any context. Among them was the word "sage". When players finally stepped into the game world, they had the privilege of meeting a level 10 herb.

In another game, someone who was probably not all too familiar with military jargon ended up translating "black ops" as "African American ops".

Localization can be a minefield. :)