The centralized state is a monster that always seeks to expand its power. We'd be even better off returning to the Articles of Confederation. Of course, that agreement of unanimous consent would not work well for 50 states, but it would work well for smaller groupings of states. The problem, then, is to reign in the modern central state so that the individual has more room to breathe and live his or her life free from oppression. That's a noble cause, but it's a strategy that hasn't been working very well.
Secession is a strategy worth keeping on the table.
In the best-case scenario, secession would divide the nation along cultural lines that already exist. Some people would move across lines to where they felt more comfortable. The south and west would probably adopt a less intrusive central state, with more local control and more individual rights. The coasts would probably adopt a more aggressive central state. Such an outcome would probably achieve more freedom than the is possible now.