There are definitely circumstances where it would be justifiable...mostly involving widespread abuses of human rights, a federal government that routinely favored one region of the country over others to a large degree, or complete cultural alienation from the rest of the country. None of those situations seem likely to occur in the US anytime soon.
As for the legality of secession...I've always thought that that question is kind of meaningless. By definition, if a part of the country wishes to secede, it no longer wants to recognize the legal authority of the federal government, so whether or not secession is "legal" is a moot point. Let's not forget that the American Revolution was illegal, and that our Constitution was passed in a very unconstitutional manner.