What is the best way or letting someone know you're not interested?

Say “I’m not interested in a relationship.”

Breaking off contact instead of informing them is kind of rude IMO.

It’s been my experience that you should be a blunt as possible. A polite message is all nice n stuff, but some people just don’t get it. Don’t leave room for confustion, tell it straight up!

I always let people know that it doesn’t seem like it will work out, for whatever reason.

Polite but blunt. Be nice but don’t step around it.

If you have to say it to the same person more than once, be increasingly less polite and increasingly more painfully, obviously blunt.

Start friendly and noncommittal. “I don’t think it will work out.” “I really didn’t feel like there was a spark between us.”

If they continue to try for romantic contact, ignoring your reasoning, get more direct. “No, I’m not interested.” You can also add, ”....and you don’t take no for an answer gracefully” to your list of reasons, as well.

If that continues further, then your best bet is to break off all contact.

Good answers above.
Just a comment for the ladies:
When you tell a guy, “I don’t think it will work out” or “This is not going to work”, don’t be surprise if he asks, “Why?”. Ladies, this is usually not meant as an aggressive stance, it is just the automatic reaction of most guys to want to know why something does not work. If you tell him, “My car will not start”, or “Hey, my TV remote will not work”, most guys will say “lemme take a look at it”. It is our genetic urge to fix things, whether we have a clue as to how to fix them or not.

This probably isn’t the best approach, but I just ignore the advances and act like I don’t notice or laugh them off until they get obnoxious. Once they get obnoxious, I have no problem just being like, “Please STOP. I am NOT interested.”

I someone asked me why, which has never happened, I would be happy to talk to them about it.

I think it really goes on a case-by-case basis; some people will be able to pick up cues more easily, some will take a little more time or bluntness. Just don’t be rude; it makes you look like a jerk, and even if they really don’t get it, there is always a nicer way to say something than being mean.

Honesty. Anything else could be leading them on.