I highly recommend reading Anna Meyer's blog post that Pollution linked to above. I started with a very large high-resolution world map and just started putting pins into it. When zoomed out, it looks very messy, but due to the resolution I can easily zoom into an area to to look at the pins in that area.
But I wish I had done something more like what Meyer did. It makes things more manageable, but instead of a grid system, what I am planning on doing is:
In my "Known World" topic have a the map with high-contrast borders for the major realms and regions. Each realm would have a single pin that would be linked to that kingdoms topic. I may have some special borders for major regions that span kingdoms or are outside of kingdoms, but I will try to be very conservative here to avoid making things too messy.
Then in the realm's topic, I would have a map with the borders of the provinces, states, etc. highlighted and pin in each area linked to that province's, state's, etc. topic. Some of the major cities would have pins at this level, but again, I would try to keep it spartan.
At the state, province, etc. topic I would have a map which would have pins to cities and some major areas.
Beyond this, things get fleshed out as the campaign progresses. I use hexographer to keep the fleshing out simple and add the maps to appropriate topics in Realmworks.