Let me begin by acknowledging my own biases on the matter: I use and like the serial comma, I have no use for the fiction or 'philosophy' of Ayn Rand, and I do not believe in God. That said, I am nonetheless going to argue here in defence of the hapless—and perhaps apocryphal—writer who, eschewing the serial comma, allegedly wrote the sentence below:

  1. I'd like to thank my parents, Ayn Rand and God.

Some people quote this sentence merely for amusement; others quote it as evidence that the serial comma is a Good Thing, even an indispensible thing. The point, of course, is that without the serial comma, the intended three-item list can be misread as a noun phrase ("my parents") with an appositive ("Ayn Rand and God"). Stick in the serial comma, and the ambiguity goes away:

  1. I'd like to thank my parents, Ayn Rand, and God.

Those who insist on the serial comma appear to have a strong case, and they are certainly in good company. Here, for example, is what the Chicago Manual of Style (15th ed., section 6.19), has to say about it:

When a conjunction joins the last two elements in a series, a comma—known as the serial or series comma or the Oxford comma—should appear before the conjunction. Chicago strongly recommends this widely practiced usage, blessed by Fowler and other authorities (see bibliog. 1.2), since it prevents ambiguity.

CMS does not explicitly mention the Ayn Rand sentence, but you can just see it lurking there, behind the words "prevents ambiguity." The trouble is, the serial comma does not always prevent ambiguity.

If we want to evaluate the utility of the serial comma at all seriously, we really have to consider more than one example. So let's suppose, for the sake of argument, that the poor author quoted above had had help from only one parent, rather than both. She or he might then have written (3), without the serial comma, or (4), with it:

  1. I'd like to thank my mother, Ayn Rand and God.
  2. I'd like to thank my mother, Ayn Rand, and God.

Now all of a sudden it's the version with the serial comma that is ambiguous, and that gives the reader a chance to imagine that the author sprang from the womb of Rand. I concede that the appositive reading here is somewhat less salient, and a great deal less funny, than in (1), but the ambiguity is there.

The moral of the story is that in writing, as in nearly everything else, there is no substitute for judgment. The serial comma cannot save us from ambiguity, nor can its omission. The only way to avoid ambiguity is to look at what you have written to see whether it clearly and unambiguously says what you want it to say. If it does not, then you rewrite it until it does. (Unless, of course, you prefer to embrace ambiguity: "Let it have two meanings," jrn suggests in a /msg, "the world will be richer for it.") For instance, the two-parented serial-comma eschewer might want to go with (5), and the one-parented serial-comma user might want to use (6):

  1. I'd like to thank Ayn Rand, God and my parents.
  2. I'd like to thank Ayn Rand, God, and my mother.

Punctuation is a matter of convention, not of logical necessity, and a dispute between rival styles can seldom be resolved by reason alone. (There are exceptions in the extreme cases—for example, prose that does not use punctuation at all will inevitably contain more ambiguities than prose that does.) One cannot hope to be Right about punctuation in any absolute sense; the best one can do is be consistent, so that the reader will know what to expect. Me, I choose to use the serial comma, and so if you ever catch me writing the sentence in (1), then (a) you will know with absolute certainty that I mean it as an appositive, and (b) please shoot me.