The Sharpsburg/Shepherdstown area is a significant one. First of all, the canal was run from its headquarters in Sharpsburg and the people who ran it lived in either of these two towns. Secondly, the Battle of Antietam is a National Historic Park and it is in Sharpsburg. Thirdly, there's Barron's store right nearby where you can buy ice cream and Gatorade, but maybe that's just a personal favorite!
To get there, start at the intersection of interstates 70 & 270 in Frederick. Take 70 West to Braddock Heights and then pick up 40A to Boonsboro. Route 34 South will take you through the heart of Sharpsburg and finally to the canal where there's a small parking lot. Download the PDF for complete driving directions.