Is it a single amp head or dual?
How many watts @ 4ohms?

With a solid-state (transistor or MOSFET) amplifier there is no "mismatch" between your amp out and an 8 Ohm load. The only thing that you lose is power. The "4 Ohm" rating on the amp is a minimum resistance, and it should give the same sound driving 8 Ohms up to the point where it runs out of volts. Valve (tube) amps are different and need the correct load, but they almost always have alternative taps on the output transformer for driving different loads.

If there really is that much difference in cabinet sound between driving all 4 units and only 2 of them, the problem is more likely to be with the cabinet or its internal wiring.

The 4 drive units are probably 8 Ohms each, so any 2 of them in parallel would make 4 Ohms. Put 2 of the paralleled pairs in series and you get 8 Ohm total. That's what the normalling contacts on the jack sockets will be doing.

I have seen cabinets that have been mis-wired in this area such that the two pairs are out of phase. Try the following check: unplug the cabinet from your amp and take a lead to the 8 Ohm input jack. Arrange things so you can connect the other end of the lead momentarily to a 1.5V torch cell using one hand, and with the other hand feel each of the speaker cones in turn as you connect and disconnect the cell. They should all move in the same direction. If one pair moves in and the other moves out when you connect the cell, you have found your problem.

If that's not the problem, you may have to try other amps driving the 4 Ohm and 8 Ohm inputs in turn to see if they produce similar or different sounds.

Some amplifiers can be loaded down to 2 ohms. That way you could parallel wire all four speakers if they are 8 ohms each. Or you could put two pairs in the series and then wire the two series pair in parallel. How about wiring only a single speaker in your cabinet so that it sounds good? You can leave the other three as spares. Have you considered going to a doctor to see if you could obtain a second penis since 2 could be better than 1? I'm sorry, that was uncalled for. You don't even need one.

Don't have one
Mx. Remy Ann David

I'm not even sure what to say to that Remy... but thank you :D / :(

You could try the 2 ohm route but that can get pretty hard on the amp....
Sorry i couldn't resist...

Well, if you STILL ( I realize this thread isn't 'current') haven't worked out the bugs, Gtrfreak, then I'd ask what's the amp make/model and that of the cab (besides being a Mesa)

OR, can you post pics? Trouble shooting always goes better when you're 'looking' at the problem....

That said, Boswells point;
If there really is that much difference in cabinet sound between driving all 4 units and only 2 of them, the problem is more likely to be with the cabinet or its internal wiring as well as Remys similar (though awesomely graphic) point should be addressed.
Do you NEED to run all four?
I too, am a guitar player. A dirty, rough edges tube driven guitar player who LOVES the look and sound of a full stack. I own 9 4X12 cabs (hush it, Remy), driven by three separate amp heads. My stage rig is a 5150 head on top of 4 cabs, with the other guitarist running the Peavey Classic 100 on top of the other 4. And even I have to admit: I only really NEED to plug in one of those cabs. Hell, a couple of the slant cabs only have two live speakers in them, so sometimes I'm only running what is essentially a 1/4 stack.
Sound-wise, I tend to prefer running just one cab. It's only outside or on bigger stages do ever get around to plugging in two or all four of the cabs, and that has less to do with 'tone' as it does just coverage.

So, that's worth asking yourself. And if you're still having issues with it all, post your gear and we'll help you find some 'real' answers

sean