The problem with putting together a new game world is that once you start applying an existing game to it is that the game's content begins to bend the world to it's will. With D&D type games there are two or three main parts of the rules which will bend your world: classes, monsters, and maybe spells. A fourth part is deities, but those are not so hard-wired into the rules and thus are much easier to create in line with your creative vision. The problem is that using the same old D&D elements makes your game feel like every other game everyone's played in.
So let's talk about the monsters. A lot of us who have played D&D before know that at any particular level you'll most likely be facing "level appropriate" monsters. Thus you've met loads of giant rats, kobolds, orcs, goblins, and gnolls before because that's what you'll face over and over again at lower levels. But I want to run a game which isn't dominated by the classic/stereotypical monsters. So what are some alternatives?
- Re-skinning: keep the original stats but come up with new graphics, new names, and a few tweaks to add new flavor; reskin goblins as the Baruka, a race of cunning weasel-people
- Re-culturization: keep the monster but give it a whole new modus operandi; orcs are a conquered native race serving their colonial elf masters
- Third-party monsters: there are plenty of published products and stuff online (like on one of those RPG blogs) which will provide creatures your group hasn't met before
- Lesser known worlds: for early editions of D&D you could grab the creatures from Empire of the Petal Throne, for instance
- Scratch-building: most D&D games don't come with good DIY rules for building your own, but it can be done; this approach is clearly the most labor intensive but guarantees unique designs