Toss out the popular titles like One Piece or Code Geass, and what is your favorite? Don't try to bend the rules, as that kinda defeats the purpose: be realistic. Something in the top 25 rankings on mangafox, etc, shouldn't qualify.
For me, It's gotta be Alive: The Final Evolution
A strange virus is making its way around the globe, causing its victims to commit suicide. In less than a week, it's become a lethal pandemic. But for a unique few, it does just the opposite... They evolve and become "Power Users."
Taisuke Kanou and his best friend Hirose both become power users, but Hirose sides with Katsumata, a strange man with no regard for human life.
The story follows Kanou as he discovers the secret behind his powers, encounters reporters, other power users, and even the military, as he tries to get his friends back.
The basic plot isn't the most original, but it still is what I think of when I think of manga. The story was finished on the author's deathbed, and holds a certain weight and poignancy at the end that is uncharacteristic of this genre of manga. It's not for everyone, and the ending certainly isn't fairy-tale, but I like it over most mainstream stuff.
Also like Kamisama no Iuutori, because it's pretty funny in a morbid way
Record of a Fallen Vampire, because it easily beats Lelouch in terms of a tragic hero (won't say anymore, or I'd spoil the many plot twists)
Shinigamisama ni Saigo no Onegai O, because the main character is one of the best guile heros I've ever seen
What are yours?