Interesting scenario. I guess a working example could be, a CPU module with home-grown wifi on board (not from a module or expansion card), or perhaps, a high speed DAQ (e.g., DSO) with the ADC, logic (FPGA/ASIC, or CPU still) and RAM all in the same area.
In any case, you probably wouldn't be using less than 8 layers. But from 4 layers, I could illustrate some things a little better.
For example, you might place signals on the outer layers, GND middle top layer and VCC middle bottom layer. VCC varies by region, since some parts need 1.2V, others need 3.3V, etc. In this scenario, you might keep GND as contiguous as possible, but because VCC is regional, you can run power distribution traces from the power supply to each zone, and filter it individually with beads, chokes, caps large and small, etc. With this design, you don't have to worry about waves traveling around the board, because there are no transmission lines between zones.
In another scenario, you might cover as much inner area as possible with VCC (3.3V) and GND, and only distribute the other voltages as needed (perhaps you only have a few things running on 1.5V and so on). A full area plane would be nice. But it's true, it's a transmission line. How much does it matter? Well, if you're driving it from a huge bus (the example of terminating a DDR3 bus will deliver amperes in no time!), you need to consider how that bus is terminated (local bypass), how it connects (via inductance, spreading inductance), what the impedances/ratios are, what kind of bypass is distributed over the board, and finally, how local areas connect.
The impedance of a parallel plate transmission line is (d / w) * sqrt(mu / e), or for a 50 x 1 mm section in FR-4, near 4 ohms. A couple amps will easily excite that, and bypass caps should dominate (it looks inductive). Moreover, in the local area, as the wave expands from the point of contact, the wave front is less than 50mm wide, and the impedance is even higher (within roughly a radius of 16 mm). The spreading inductance is mu * h * ln(R / r) (if I remember right), which for R = 16 mm, r = 2 mm (i.e., the inner via is 2 mm radius -- or more likely, we'll say there's a cluster of vias with an equivalent circular outline of 2mm radius) and h = 1mm, gives 2.6nH. Which will be kind of troublesome for the highest frequencies and harmonics. For which, to have the bus function properly, it will need local bypass and stuff. The cutoff frequency would seem to be 4 ohms / (2 * pi * 2.6nH) = 244 MHz, so you'll still get trash up around a gig or two, coupling into the supply.
The isolation between a suitably bypassed, but otherwise quite powerful load, wouldn't seem to be too much. It's not going to be amperes on the internal planes, but it's still going to leave more than a few millivolts. Once those mV are on the planes, I don't think there's all that much that can be done about it; bypasses strewn about will perturb the fields, but will generally have too little loss anyway (ceramic caps with ESR < 0.1 ohm won't do much to a ~4 ohm transmission line). It's noteworthy that smaller tantalum capacitors have ESR of a few ohms, which is curiously ideal for adding loss to such a system. It should be no wonder why they are so popular!
Tim