Are we talking about fangames or rom hacks? Because those are two completely different things...
If it comes to fangames... The first it comes to my mind is
Pokémon Uranium (It's a fangame so I'm not breaking any rule by posting it). It's a fangame that is still worked on (the last demo had up to the fifth or sixth gym if my memory recalls correctly), centered in a new region (Tandor) and the main plot focus on something really unusual for pokémon standards: Radioctivity.
The game plot starts after a power plant accident (that happened 10 years before the game start and involves directly with the main character) and it even has radioactive pokémon on it (with their coloration changed to black and neon green to prove it), thus introducing the Nuclear type.
Other than that it has pretty fakemon on it, including evolutions for already existing pokémon (like Primeape and Dunsparce) and the starters are pretty cool looking and great typewise:
Orchynx (Grass/Steel),
Raptorch (Fire/Ground) and
(Eletux) (Water/Electric) (they only have two forms unlike any official starter, but the author plans on giving them Mega Evolutions... Mega Metalynx looks promising).
It's worth checking it out... Really, do it for Orchynx.
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As for romhacks, well... other than the already mentioned Liquid Crystal (that did a pretty great job at remaking Gen II while keeping the adorable Crystal at playable... I curse Game Freak for replacing good old Crys with the annoying and plain looking Lyra), it comes to mind the name of Drayano.
Drayano is a guy that managed to fit all pokémon in one game, changed the evolution methods in order to make them obtainable in game, retyped some pokémon (Like Farfetch'd (Fighting/Flying) or Psyduck (Water/Psychic)) while tweaking the movesets and stats of (almost) every pokémon to balance the game (thus making useful pokémon like Flareon or believe it or not...Delibird)... All of this while raising the difficulty curve a whole lotl.
He has done that for Gen III (Fire Red Omega), Gen IV (Sacred Gold and Storm Silver) and Gen V (Volt White/Blaze Black and Volt White 2/Blaze Black 2).
And there's what I like what to call the "Constellation Series".
It's a series of Japanese (sadly) rom hacks made by the same author with a new region,
LOTS of Fakémon, evolutions for existing Pokémon (such as Mawile, Girafarig, Sableye, Relicanth, Absol, Farfetch'd, Arbok, Weezing, Tentacruel...), an entirely original plot (sadly it's in Japanese) and a custom OST made by scratch for this games.
It starts with Altair and Sirius that seem to be based after Ruby, then it would come Vega (the most known of them all, check it on Youtube) which it's either a "third" version of Altair and Sirius (a la Crystal, Platinum or Emerald) or a sequel... And finally Procyon and Deneb that are sequels of Vega (and seem to be still in the making or so I've heard/read).
If you can, try Vega... It's hard as hell and only in Japanese (it has a translation patch for the move names and items though) but it's worth checking.
