If you’re working in InDesign, choose the right preset before you export to pdf.  And if you have a lot of lines (i.e. placing more than one Illustrator file), check this out, too.

If you’re working straight out of Illustrator: first, delete the layers you aren’t printing (don’t save the AI file like this – just for printing sake, because it will try to print things that are invisible and this takes longer); second, check out your options before printing to pdf (do you really need Illustrator Editing Capabilities?).

If all else fails (and your file is still massive and the plotter is angry at you and your deadline is in twenty minutes), dump it into Photoshop and save as a jpg (or something else layer-less), reopen, then print to a pdf again.

Also, for people with a Mac, as snazzy as Acrobat Reader might seem, Preview is much better at shrinking your pdfs down to a reasonable size.  Save as a pdf or jpg there, instead.

Feel free to add to this, guys.