Typically, I try to build decks so that they can account for all weaknesses, but I try to use cards with uses beyond what they are teched against. For instance, the new Dedenne can put the hurt on Yveltal players (especially ones that get aggressive with energy attachments), but it also has the useful call for family attack that helps with setting up. Druddigon is great against BKEX and other BW Dragons, but it's also a good card in general; doing 90 damage for a DCE is never bad (and at the very least, can serve as a one prize attacker). Mewtwo EX also covers quite a bit of weakness while still maintaining it's stasis as one of the most efficient attackers for any deck.
For me, the big problem is Pyroar. Some decks have built in solutions to it (Garbodor, Empoleon), but others need to rely on tricks (lasers/lysandre/alternate damage). The worst has to be Genesect; who's entire deck is weak to fire in addition to being all fire pokemon. Some will say accept the autoless, but with my luck, I'd end up facing those troublesome decks so if I'm going to play Genesect, I want to have a chance against what is likely to be a big deck. And while I haven't played it much, I think Abamasnow is the best solution. It's cost is more specific, but with a muscle band, you can take out ANY fire weak pokemon and still take out Pyroar with 2 energy.
There are other troublesome pokemon who can shut things down. Some have easy solutions (for safeguard pokemon, you can just run a non EX or 2), while others I wouldn't be too worried about (no one plays Froslass and even if they do, a single Lysandre followed by a raiden knuckle). But really, once you tech against Pyroar, a strong strategy can find ways around other strategies.