I've seen bills with slightly (key word: SLIGHTLY) smudged ink come through my register. In 14 months I've gotten two fakes, and in both cases the dead giveaway was the feel of the bill: bill paper is very distinctive, and if you handle it much at all, you can spot a fake from a mile away.
Here is the process I use at work for spotting fakes. I removed the "magic pen" that we use because while these are available at stores like Staples and OfficeMax, they're worse than useless--leave them uncapped and they'll give you false positives, spray a fake bill with hairspray and they'll give you a false negative (I kid you not, hairspray will mark a fake bill as valid).
First, hold the bill up to the light: on the right-hand side there should be a watermark that appears lighter than the surrounding bill. Dark, clear watermarks are actually a picture printed on something similar to tissue paper and sandwiched between layers of (fake) bill. The watermark should match the portrait on the actual bill, e.g. a $100 should have an old Franklin on the right, a $20 should have Jackson looking upward, etc. Next, look for the security strip. This will be printed with, for example, "US 50 US 50 US 50" (on a $50) and will be to the left or right of the portrait, depending on the denomination.
Finally, run your thumbnail over the President's (or Franklin's) coat. On a real bill, even the small portraits dating back to the 1970s that I sometimes get, the coat will have raised ridges (on a $20, it will be raised hatchmarking) that you can feel with your nail and sometimes even the pad of your finger.
There are other anti-counterfeit measures, but these will let you spot a fake very quickly most of the time, and if you're concerned about scaring customers or merchants (I get a lot of skittish people when I have a hard time finding the watermark), the thumbnail test is quick and unobtrusive.