Warning: Potentially controversial and offensive material, especially to people with strong religious / spiritual beliefs.
It should be obvious that as a fan of SEIV, MOO, Star Trek, Star Wars etc., I enjoy the idea and fantasy of huge starships moving across interstellar distances. But I have to say that I don't believe that it'll ever be anything more than a fantasy. The immense physical / energy problems is one thing. The economic cost / benefit rationale of such an endeavor is another. But perhaps the most overlooked obstacle to such a vision is that humanity may not stay in its current form for every long.
At the very least, one would expect severe genetic / bionic modifications to function optimally in a spaceship, because the energy costs of genetically / bionically modifying a human being is so much less than the costs of moving a ship at respectable velocities. A good example would be the type of modifications described in the short story
"Spirey and the Queen" by ALastair Reynolds. This surely puts paid to the Star Trek vision of future space travel.
But why be so conservative? It's likely that within the near future, we could have fully conscious, fully sentient artificial intelligences. Rather than being wholly alien and hostile, as in "Matrix" or "Terminator", I think that the likeliest scenario would be something similar to Walter Jon Williams' story
"Daddy's World" , i.e. they'll just be like us, being our offspring. Once conscious software has fully legal rights, I expect that people will start designing, rearing and interacting with software children instead of biological children. A spaceship carrying conscious software has very notable advantages over one that must carry biological lifeforms. In Greg Egan's
"Diaspora" for example, "polises" that are physically only about the size of a shoebox, but containing untold billions of independent software persons in VR environments, multiply backed up and constantly updated with similar units with old-fashioned EM communications, creep across the galaxy.
Instead of sending huge colony ships across the galaxy, how about sending non-intelligent software controlled robots to build the necessary sensory, power, construction and communications infrastructure on distant worlds, and then sending future humans to inhabit them in the form of encoded EM radiation. After all, if materialism is true, then person-hood is nothing but data.