This isn't so much a 'versus' thread about certain brands, it's just that I'd like to know whether there's a significant difference in sound if you run a 4x12 cab through your head (let's say at 16ohms) or two 2x12 cabs parallel (so 2x8ohms).

I've currently got one 2x12 cab and have been thinking about getting a 4x12 as the band I'm playing in is getting more serious, but it would be far more practical in weight, transportation and costs if I get a second 2x12 and just stack them. I can change the speakers in either cabinet to match each other if I don't like the combination. I've been leaning towards a second 2x12 but I'm not too sure whether or not a 4x12 will sound a lot different. Does anyone have advice/ideas/an answer? Thanks
It depends on the 4x12 cab and the 2x12 cab.
I would just get another 2x12 if you have one already then you have the best of both.
2002 PRS CE22
2013 G&L ASAT Deluxe
2009 Epiphone G-400 (SH-4)
Marshall JCM2000 DSL100
Krank 1980 Jr 20watt
Krank Rev 4x12 (eminence V12)
GFS Greenie/Digitech Bad Monkey
Morley Bad Horsie 2
MXR Smart Gate
Nope, doesn't make much difference whatsoever. Although in the situation you described, it would be 4 ohms for the 2 2x12 cabinets versus 16 ohms for the 4x12.

"Show me war; show me pestilence; show me the blood-red hands of retribution..."
I personally prefer 2/2x12 versus the 1/4x12 when I have the option, I find that there's a lot more clarity and the bass frequencies are much more punchy and focused, leaving more room for your bassist to fill in the tonal 'gaps'. this being said, a single 2x12 and a 4x12 stacked is the most fun (IMHO) because you can really beef up your tone (especially with different speakers in each).

Just a thought. the latter also allows for speaker selection for venue size difference.