I think we know much of what we need to know (the basics: how to procreate, how to create a craft, etc; plus the steps to take) but the costs are just a little hard to justify for many given existing world problems and a predilection to just fighting everything.
If it is a generation ship or some other from of slow craft (and aren't they all at the scales we are discussing), then it needs to contain a biosphere if it is going to take humans in their current form. We aren't anywhere near good at making those at all.
Unless we are thinking about some form of entirely synthetic food and oxygen production, in which case, we aren't any better at those really.
