The biggest challenge I've seen for any extended storyline, especially with graphic novels, is keeping the story interesting and fresh. Fables is a good example of how it's not always successful, and Sandman is a good example of ending a story when it's at its peak, and now The Walking Dead is a good (possibly great) example of how to keep a story engaging and new, nearly 150 issues into its run.
Rick Grimes and his crew have been through a lot, but they key to the entire series so far has been survival. Kirkman himself has said that how the zombie plague began is of little interest to him, since the stories of the survivors are where he wants to focus his attention. Since Team Grimes has proven to be adept at surviving all that the zombies have thrown them, the challenge for survival comes from the other antagonists that come to challenge them. First there was the Governor, and then there was Negan; after they've settled in, and learned how to live a civilized life, now they're faced with the Whisperers. And I'll be damned if, while they're not as ruthless as Negan, they're a whole lot creepier.
The other interesting thing about these antagonists is that they're not caricatures, nor are they stereotypes. Kirkman gives them a believable ethos to carry them through the brutalities they commit. None of them are sympathetic by any means, but you can at least understand where they're coming from. Kirkman doesn't throw them out there without reason; their motivations are their own, and make sense within the constraints of the story. I think that's why they resonate beyond the stories themselves.
With the last two collections, since Team Grimes created their own little utopia, I was concerned that the story might take a different turn, or let me down. With Life and Death, I'm reminded why I need to give Kirkman more credit. I highly recommend this volume, though you'll need to commit at least to the previous two collections to get the full story.