Okay, I’ve (probably) done just enough reading since asking this question, and apparently this combo of anti-spam plugins, works to a very appreciable extent in mitigating spam:
Akismet + Cookies for Comments + Impostercide
Knowledgeable people agree:
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Alex aka Viper007Bond uses Akismet and Cookies for Comments on his own blog, alongside having Trackbacks disabled. (Source)
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Donncha O Caoimh says (via email), “I use cookies for comments and it works just fine with WP Super Cache!” — He also happens to be a co-developer of a number of anti-spam plugins. He also, most probably, uses Akismet.
The need for the use of “Impostercide” plugin should be obvious, unless the email you administer your blog with is unknown to the world, or you just don’t care even if the spammers post comments on your blog using your Name and Email (and hell if you use Gravatar).
And yes, this setup may not fit everyone. Especially those blogs that want to enforce a stricter set of rules and techniques.