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I've always considered Shredder, Krang, Bishop and Null at the best "Big Bads" of TMNT-lore.
Shredder for obvious reasons, Krang representing the best of the outer space/inter-dimensional aspect of TMNT (Maligna and/or the Triceratons coming close second), Bishop representing Splinter's fear of the outside world, and Null (both Mr. or Madame) being that mysterious unknown factor who's grand scheme is ambiguous in places.
Other villains (Dregg, Stockman, Rat King, Romero etc), while I do like them, I always seen them more out side-antagonists than real big bad (though Stockman has come close in places, 2K3/IDW wise).
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