The biggest problem, of course, is the economic incentive: No Bucks, No Buck Rogers. A man-rated space plane just isn't economically viable.
Rockets are dangerous... there's a quote attributed to Von Braun that goes, “There is a very fine line between a rocket and a bomb...the finer the line, the better the rocket!” If you put a human being on the rocket, everything gets much more complicated as you try to keep that bomb from going off. Make that man-carrying rocket capable of operating in space and you've made your design problem much more expensive. Demand that the man-carrying rocket also function as an aircraft, and the price tag goes up even further. Add to that the need that the spacecraft needs to re-enter the atmosphere at Mach 25, and shove the decimal point a few more spaces to the right.
Now... to those design requirements, add the need to make the system reusable...so that you can recover the "bomb," refurbish it, put humans back into it, and shove it back into space with no additional risks over that of the first flight.
So, you've got your Shuttle Mark II sitting on the ramp ready to fly. How will it earn back its multi-billion-dollar price tag? Note that, depending on the satellite size, a customer can currently put its spacecraft into orbit for $25M or so. How do you compete with that?
Transportation to the Space Station? The Russians do that quite comfortably and quite cheaply now, with 1970s technology.
The only thing left is space tourism. It sounded like a great idea in 2005, but how has the current economic conditions affected the market? The vehicles can be much cheaper because they don't have to re-enter at Mach 25, but their use is limited to thrill rides. Performance-wise, they're as good as Mercury-Redstone...fifty-year-old capability that NASA abandoned in 1961. We can remember the "Barnstormers" of the 1920s fondly, but it was the carriage of mail and passengers that eventually brought aviation into the mainstream.
I love space (been working in aerospace since I graduated from college 30 years ago), I love the Shuttle, but the sad truth is, a replacement is no more economically viable than the Shuttle itself was.