If you’re working in an environment with a noisy background, Skype’s über-friendly automatic gain control can drive you crazy (open up sound preferences and watch your input levels change like magic)

Here’s a fix (that still works in Skype 5):

http://jon.smajda.com/2011/04/19/disable-automatic-gain-control-in-skype

tl;dr?

Open up ~/Library/Application Support/Skype/shared.xml in a text editor, find the <VoiceEng> section (w-a-a-a-a-y at the bottom), and add <AGC>0</AGC>. Like so:

<VoiceENG>
  <AGC>0</AGC>
  ... [One or more <MicVolume>'s. Leave them alone.]
</VoiceEng>

P.S. If you did read the article, <EC> is the Echo cancellation mode. I like to leave it on, but YMMV, especially if you’re wearing headphones and have no need for it.