Some of the most important works of art of Western Civilization are held within the Vatican's walls and to experience them is sublime, but there are several key points to remember.
Expectations of a Museum: The Vatican is not actually a museum; rather, it is a *private residence* that is opened to the public, so don't go there expecting the typical wall labels and explanatory text or the chronological or thematic organization of a scholarly museum. The art was arranged to impress visitors to the Pope's residence, so don't be whiny or nasty about it because the Pope does not have to let us visit.
Lines: There are two lines. One is for tickets. The other is for security. A tour group bypasses the ticket line. On the last Sunday of the month, you won't need tickets, so you only wait in the security line. You can purchase tickets online before you go, but you still have to wait in the security line. It can still be long, so give yourself at least 45 minutes to wait in the security line, even in the off season.
Sistine Chapel: Be careful to double check that there isn't some big event or private function going on in the Sistine Chapel on the day that you plan to go. Because this is the Pope's place and the Chapel is still a functioning chapel, they sometimes close it to the public when he is performing Mass there or has guests there. You can take photos in some places, but not in the the Sistine Chapel. The Sistine Chapel is utterly packed full of people and could be overwhelming if you travel with children, so you might want to prep them before you go. You are not allowed to talk in the Sistine Chapel, since it is a functioning chapel. Do your chatting and explaining before you enter the chapel. The guards will shush you. I saw one walk right up to a loud, talking tour guide and heard him give the guide what for. There is a bench that lines the walls, but it is crammed full of sitters. If you turn your back to the entrance, you will notice two exits, one on the right and one of the left. If you exit to the right, you will take a shortcut to St. Peters and won't have to go back out and go through security again for St. Peter's.
How much time do you need: At least three or four hours. The entire place is packed from floor to ceiling and wall to wall with art, so if you are going there to view everything, you should reserve at least a couple of days or visits to view it all. I suggest choosing a few key pieces of art that you don't want to miss and just focusing on those. Otherwise, you will be mentally exhausted before arriving at the Sistine Chapel. If you are not using a tour guide, then do your homework before you go and find out where your favorite pieces are. We used a tour guide, Sara Magister, through Context Rome and it was worth every penny.
Other Thoughts: Eat a good breakfast, drink a few espressos and put on your best walking shoes before you go. Take water and some crackers and enjoy. Don't use your flash on paintings or textiles! You will destroy the art for future generations. There are massive amounts of people there, even during the off season so be prepared for that. Don't forget to visit St. Peter's afterwards.
This review is the subjective opinion of a TripAdvisor member and not of TripAdvisor LLC.