There are lots of possibilities. The biggest hurdle is finding ways to get into high orbit cheaper.
It all boils down to the gigantic gravity well of the Earth. I don't know the exact numbers, but I'd guess it takes a hundred tons of fuel to lift a ton of cargo into space.
That will never be cost effective.
It will truly take pioneers. People willing to depart Earth for long term: years, perhaps even decades or their entire life. People willing to settle in orbit or on the Moon. Willing to take their families and begin real colonies.
Dangerous? You betcha.
But so was Roanoke. And many other colonial voyages.
One other thing that strikes me:
Heavy lift (Saturn rockets, Space Shuttle System, etc) is much more dangerous than modern lightweight manned vehicles like the X15 or SpaceShip One. It's also more expensive to launch.
A lighweight orbital "commuter" project would be fantastic... keep your payload stuff on heavy lift systems, but send up your astronauts in devices that are slower to ascend, and operate more like a plane than a rocket.
Loss of payload? It sucks, but it doesn't cost lives then. Also cheaper and faster to rotate crew on and off of orbital stations.