In my opinion, third parties could make the biggest difference at the local level, but most of them don't really seem interested in local politics. I also think it would be a good thing for third parties to be taken more seriously at the national level.
One way to get voters to think more seriously about third parties would be to have their candidates participate in the debates with the Democratic and Republican candidates. Unfortunately, the way the rules are currently written a candidate has to be polling above 15% for a certain period before the debate. This pretty much means that no third party candidate is ever going to participate.
I think one change to the debate rules would help solve both of these problems. Instead of a polling threshold, use an officeholder threshold. The one I thought of is allow any political party that has constantly had a member in office at the state (state legislative bodies, Governor or other state-wide office, judge [if they're elected and declare a party affiliation]) or national level (House or Senate) for the last 5 years to participate in the presidential debates. I might even count mayor of one of the 10 biggest cities in the country. If that leads to an unwieldy number of people on stage, than either increase the number of officeholders or the amount of time required.
This would help with what I feel is the biggest problem, by giving the third parties a strong motivation for getting people elected to lower levels of office. It would also help with the secondary problem by making it more likely that a third party politician who doesn't have high name recognition would be visible in the presidential campaign.
(Edited to remove some the "I thinks." There were way too many...)