There is one disadvantage I know of, but it's a biggy: waiting. It can take as long as a year for a journal to turn around a paper, and if you do this several times, it can be very aggravating. I recently had a paper accepted on its third go-round, and while it still got in a pretty good journal, the whole process took about 2 years. In particular, I went on the job market with this paper as a pre-print rather than an accepted paper as a consequence. I doubt this fact was consequential, but obviously it would have been better to have had it accepted.

That said, I always aim high (within reason), and generally think it's the right policy. There's so much uncertainty about what belongs in what journal that one might as well give it a shot.