Sex & Nudity
Several characters are in relationships, some of which are homosexual.
In the episode Genderstorm, pretty much every character is temporarily changed to the opposite gender.
In the episode Slumber Party Panic, one of the party games is gay sex, although barely any characters participate in it.
In the episode Madcap Mess, Makoto and Kyoko are seen wearing swimsuits at the beach. In particular, Makoto's swimsuit was intended to be more revealing, but was changed at the last second to offer more coverage.
Some slapstick violence.
Characters occasionally get in fights with one another.
In the episode Hauntings, the quick frames display brief scenes of violence.
Marco commits suicide in Season 4, but the death itself is not seen.
Duke Nukem owns guns and sometimes (albeit rarely) shoots them at people.
Most episodes have swear words in them, although all of these words are censored.
In the episode The Jellicle Ball, Callie Briggs calls Shimbleshanks "a fucking railway asshole."
Drugs & Alcohol
Cleo is seen making cocktails and other alcoholic beverages in numerous episodes.
The plot of the episode Mushrooms focuses on Pixel and Lixep taking drugs. One of the lines Pixel says in this episode actually led to two teenage boys committing suicide, although the line was omitted in later airings of the episode.
Some tense scenes and arguments.
On TV Central, all episodes of the show are rated either 3 Yellow Stars or 4 Orange Stars.
On RandomTV, all the episodes are rated either TV-14 or TV-MA (including subratings).