In one sense, the title suggests something pretty obvious – someone once felt comfortable and is now feeling uneasy. And actually, once you get into the novel, you find out that this quick assessment is accurate. The title reflects the discomfort felt by the main character, Obi Okonkwo. His university education in England has left him feeling alienated from his family and friends. While in England, he was alone in a foreign place, thousands of miles from his family, speaking a foreign tongue. And besides all that, he comes from a warm, tropical place, and needs to adjust to living in cold, foggy, rainy England. Obi can no longer get his mother's pounded foo-foo, yam, or fish soup. Instead, he's had to adjust to eating boiled potatoes, boiled meat, boiled vegetables.
But that's not exactly Obi's problem. It gets a little more complicated than that.
The problem of homesickness is compounded by the fact that Obi partly rejected his own culture, embracing Western values through his Western education. As a result of his Christian upbringing (see our "Character Analysis" of Obi's father, Isaac for more on this), and his British education, Obi decided that the written word is the way to go. He suddenly found himself believing in democracy and thinking that if you want to get ahead in the world, you need to be a Christian, read and write proper English, and behave like a European.
So Obi tried. But that doesn't mean he felt comfortable in England. There he was, studying in an alien culture, feeling uncomfortable and different. However, when he returns to Nigeria, not only does he not fit in with his fellow countrymen, but he's also uncomfortable among the English expatriates in Nigeria, even though they all work together and they're supposed to be buddies. So, he doesn't feel comfortable with his own folks and he doesn't feel comfortable with the other guys, either.
Obi's estrangement from his culture is the same problem that thousands of young people in Africa and India faced after their Western educations. They are at odds with their own culture, but at the same time they are at odds with the new culture that they had (partly) embraced. On the one hand, they saw all sorts of problems with the culture they had left behind; on the other hand, they weren't accepted by the Western culture they had tried to embrace.
This is a phenomenon explored by many postcolonial writers. Colonial powers expended a great deal of effort and energy towards distinguishing between Western culture and colonized cultures; Western literature, philosophy, and popular culture portrayed colonized cultures as "inferior." Young people from colonized countries felt estranged from their own culture after their Western education, even while they were not accepted by Westerners. This condition has been called a "postcolonial identity" and Obi exhibits a classic case of it.
(If you're interested in learning more about postcolonial identity, we recommend you check out Albert Memmi's The Colonizer and the Colonized, Edward Said's Orientalism, and Gayatri Spivak's "Can the Subaltern Speak?")