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Depends on What You Want
If you're just looking to make tracks to St. Louis, then your best bet is to just head up I-270 out of DC to make the connection to I-70 as soon as possible at Frederick. If you're looking for a little more scenery and can spare an extra couple of hours, then you want to leave Washington on I-66 to I-81 south to I-64 which will take you the rest of the way to St. Louis. One final option is to start out on I-270/I-70, but to switch over to I-68 at Hancock, MD, and then use I-79 south to Charleston, WV to pick up I-64. I've driven all three, and when I have the bit of extra time it takes, the last option is my favorite.
AZBuck
