... Does the load hit all speakers evenly? I.e. does series or parallel matter here? or if you have 4X50W you just get 200W of handling? ...
For practical purposes in a guitar amp:
Yes, No, Yes.
... any speaker in the entire chain of the loop (series or parallel) takes part of the load. ...
Yes.
... in parallel the two sides dont' guaranteed have equal resistance/response/imedance and therefore one half can end up taking a bit more of the brunt of the load ...
My recommendation assumed we're talking 4 of the same speaker. If you have mixed speakers, the ones which are most efficient will be louder than the others and could mask them.
We're assuming the "cab for a 100w amp" isn't using 3 50w speakers and 1 10w speaker; if you did the 10w speaker would tend to blow first. But you intuitively know that's a silly idea.
You may need to practice basic electronics figuring with some Ohm's Law puzzles. Replace the "speakers" with "resistors". If we have 4x 8Ω resistors in series-parallel, there are two branches of the circuit with two 8Ω resistors in series. These can be simplified to two parallel 16Ω resistors, which could again be simplified to a single 8Ω resistor as a load.
If you adjust the values of any of those "resistors" within a reasonable range, you'll find the power dissipated across the changes very little. It's probably good practice to figure the current through and voltage across each of the resistors. So production tolerances don't amount to much change in-use.
... in parallel the two sides dont' guaranteed have equal resistance/response/imedance and therefore one half can end up taking a bit more of the brunt of the load, thus why 2x is generally advised, because you can't guarantee equal loading.
No.
Volts-RMS is converted to Peak volts as √2*Volts-RMS; Current-RMS is converted to Peak current as √2*Current-RMS. Power equals Voltage * Current. For a sine wave, average power is equal to RMS power, and the power implied by the peaks is a brief instant.
But if you distort a sine until it is a square wave equally-large (the square's peaks are as-tall as the sine's peaks), the RMS power of the square wave = √2*Volts-RMS * √2*Current-RMS = (√2*√2)*Volts*Current = 2*Power RMS of the sine wave.
You rate the speakers for 2x the rated clean power of an amp because if you distort it hard enough, it
will kick out twice the RMS power to the speakers. 100w of speaker load will burn up fast in such a situation with a distorted 100w amp.