Even if you make it easy to unsubscribe (one click, no sign-in, prominent link), sending an email to any large number of people will still result in "mark as spam" being used on a surprisingly large percent of messages.
Where I work, we send mail through Amazon SES, so we get digests of all the messages that have been marked as spam (stripped of identifying email headers). We see it used on (marketing) newsletters of course, but also on welcome messages; transactional messages (both the "action required to receive money" and "you owe us money" type, though the latter get marked as spam much more frequently); password reset messages; and pretty much anything else we've sent out more than some middling-to-large number of times.
To help deal with this, we include a token in each message and process the digests so marking a message as spam will unsubscribe you (or disable the notification). It's not ideal from our point of view - because we are presumably getting dinged by the mail provider when someone marks a message as spam - but hopefully it helps in the long run since we don't send more messages that will likely just get marked as spam.
When I mark something as spam, I'm doing it to penalize the sender. Whether they made it hard for me to unsubscribe, bought my email from someone else to spam me (hooray for "+blah" gmail aliases), or whatever else - I see it as a different action than unsubscribing. I'm not sure, however, that this difference is commonly perceived. It seems like there are a lot of people out there that use it much less judiciously.
Occasionally I will mark a message as spam in Gmail and get a dialog asking if I want to unsubscribe instead of mark as spam; though I only recall this happening with messages from Google properties. It would be nice (though possibly ripe for abuse) if there was some way to let Gmail know where the unsubscribe link is in the message, so third parties could take advantage of this feature. That way the user could be a little clearer about whether they are punishing the sender, or just want the message to go away.