I am sorry to see the monster fighters theme disappear, but I guess TLC have pretty much covered it now. I still think the whole horror/monster theme is a really good one with lots of possibilities. And kids love monsters.
Personally I think we need an ocean/underwater theme, something that would bring us sets with diving equipment and crafts, submarines, deep see divers, underwater creatures. The flagship set could be something like the legendary sunken city of Atlantis or a deep water research station like in the movie "The Abyss".
I think there are lots of possibilities in a theme like that.
Also I think an arctic (or antarctic) theme would be interesting. Lots of possibilities for vehicles and equipments, polar research stations and outposts, polar bears, whales, snowmobiles, etc. That would make for interesting story lines as well.
After the failure of the Pharaoh Quest, I am hesitant to suggest a theme that would be based on the ancient civilizations of America, like the Aztecs, the Mayans or the Incas. Lots of possibilities there too, big buildings (pyramids), some mystery, superstition and magic surrounding all that, some Spanish conquistadors and their ships to add a little bit of conflict into the mix.