Well a show with an alien as it's lead can work. After all the lead character in Doctor Who, The Doctor is an alien, true he happens to look human, but you could have a human looking alien Captain in Star Trek.
True, but, two things about that.
1. The Doctor isn't really alien at all, is he? I mean, sure, he's a "Timelord", but he always looks human and he makes more Earth (mostly British) references than his companions do. His alien-ness is mainly his second heart - which seems to just allow him to feel MORE human feelings more strongly.
2. There is almost always a human companion for us to see the goings on through the eyes of. The focus character for those rare occasions when the Doctor really IS acting strangely.
I do, however, think that Sran
's idea about using an alien that has some reason to also explore his or her "humanity" - Worf raised by humans, Data wanting to be human, so on - has merit and might work. Might. A lot would depend on the writing. But then, it always does.