The human experience thus far has been largely one of working within limits. The human psyche and cultures seem quite well adapted to coming up with incredible results while working within some set of rules. These rules are what make much of our activity meaningful -- a football game would make no sense if there were no rules as to how it should be played. Many of our most important creative works gain their appeal from going so far while constrained by sometimes artificially severe rules (my favorite example is some of the complex models, such as anatomically correct insects, that can be made in purist -- one square, no cutting -- origami).
The rules are frustrating, to be sure (and indeed, that's the point). So it's no surprise that we dream of being able to more or less set them aside, especially when they're rules we find ourselves forced to live under (such as the laws of nature). That's where transhumanism comes from -- a desire to set aside those pesky rules and quirks that constrain human nature. Yet at the same time, the notion of rulelessness evokes the feeling of creepiness in those of us who aren't filled with a desire for freedom. We don't know how to operate in a world without rules as constraints and reference points.
This feeling was explored quite well in Brave New World. The reader is creeped out, but left without much rational disagreement, with the practices of the future society. What can we say is wrong with oppressing people whose nature -- re-created through drugs and eugenics -- is to want and thrive under oppression? Huxley's answer is a psychologically satisfying cop-out. Bernard Marx's inability to fit in to the brave new world is proof -- reassurance -- that human nature ultimately can't be changed fundamentally. Our ability to reason about the events is restored by restoring the framework of constraints we've been trained by millions of years of evolution and culture to operate on.
So the creepiness that many of us sense in transhumanism is not so much a sense that it's wrong, as a sense that we can't think straight about it.