Divide the layout into sections, subcircuits, just as you would on the schematic. (I mean, assuming you're drawing things in an understandable fashion and not just net-naming everything...

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This groups local currents together. Switching regulator has switching currents under itself, no where else. MCU has signal currents under itself, and nowhere else. Etc.
The exception is for signals entering and leaving the section. Follow a transmission line scheme. Signals can be bused together at modest separation distance, but mind that there will be some coupling between them. Which is most likely acceptable for digital signals, but you may want some isolation for high speed analog signals. Signals always flow over ground plane, preferably surrounded by it, with stitching vias as needed.
Higher level structure: try to arrange sections in a starred linear shape. Avoid making loops between sections, which will tend to pick up ground loop currents from between sections.
Ground slots, if applicable: a starred linear structure is the only way (or, well, one of the few reasonably general ways) to make use of ground slots. DO NOT cross slots with traces. So, all those buses have solid ground under/around them. Only the ground between buses can be removed, mostly without ill effect.
Example: if you imagine a layout in the shape of the letter 'E', there's a central node with three buses, one of which is a leaf node; the two corner nodes have one more bus each, connecting to a leaf node. The negative space between legs of the 'E' can be cut out, with no impact to signal quality.
If you need to connect signals from one leaf to another, you should route them back along the common bus, through unrelated nodes. Routing them directly would cause a loop.
This description implies a lot of distance between sections, but full length transmission lines are of course not necessary. As long as you can draw a conceptual divider between regions, the buses can be any length, including ~zero.
Note that a leaf node cannot have any common mode (ground loop voltage) through it -- because there is no loop there. Putting switching regulators on leaf nodes, with input and output filtering at the bus entry, is a very good idea.
The final caveat to this kind of structure is, there can be resonant modes between the physical branches of the circuit. These can still be somewhat excited by signal currents in the buses, leading to emissions and susceptibility; a good reason to have the buses well shielded in the first place. Slots between conductors exhibit monopole (slot to edge) or dipole (enclosed slot) resonant modes; these can be dampened by putting impedance across the slot in a useful area.
You don't have to worry about slot modes with a solid ground plane, another fine reason to use it. Solid ground plane also helps to short out common mode voltages, so that if you do make loops, they are less likely to be offensive. It's still a good plan to avoid making loops, following the star routing scheme described above.
Tim