Much like my previous post on setting up a forum site, I also think it’s best to separate a store function from the rest of your main site. The highest prize in hacking is really things like credit card records or other money oriented information–so to reduce the chances of all of your stuff getting destroyed in one shot you want to keep things separated as much as possible.
There are many stand alone store website packages out there. Quite a few are based on the grand daddy of open source commerce: OsCommerce. Zencart is an adaption of OsCommerce to be a bit easier to set up than the original. It honestly used to be somewhat hard to find a open source shopping cart program, but with the explosion in open source development it’s now actually difficult to figure out the reverse: which of the millions are actually any good.
I actually like a surprising choice: X-cart, which is NOT open source. But it has almost every benefit. It’s very inexpensive ($200), they give you the source code, allow you to make mods, and provide support and free upgrades forever (and have actually been producing many). It also has one of the best things I’ve ever seen in ANY website development software: Webmaster Mode. This is an Ajax sort of thing that once activated lets the admin literally click any text element of the site–which opens an editor box and allows instant editing of the content. You can speed through setting up your site in record time.
Of course the absolute easiest choice is to set up a Paypal or Amazon store, but those make you look kinda crappy in the long run. Whatever your choice, remember you need to always be on the watch for security updates, and always upgrade if there is a security issue.