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Transformers: Age of Extinction picks up five years after the Battle of Chicago in Dark of the Moon.

The Autobots

are now being hunted by the CIA and a Cybertronian bounty hunter.

Bumblebee is apparently no longer Sam's guardian, as

the Autobots are all hiding.

No mention, however, is ever made of the Witwicky family even though

they would be the humans most likely to be able to locate the Autobots.

Out of universe, the absence of the family is simply due to the cast change. Is there an in universe explanation as to why there is no mention of the family at all? Perhaps something in a tie-in comic, novel or just an interview?

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    Given his portrayal in the first three movies, I would assume Sam is off somewhere flipping burgers, slacking off, and complaining about his life. – Omegacron Mar 18 '15 at 17:32
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In Transformers: The Last Knight it's intimated that Sam was one of the few remaining Witwiccans.

However, emphasis on was, as Sir Edmund Burton indicated a couple times (once to Cade and Vivianne, once to the Prime Minister) that he himself was the last Witwiccan (except maybe Agent Simmons, now).

This seems to indicate that Sam Witwicky, descendant of Archibald Witwicky, has died since his last appearance. Perhaps during the Witwicky Incident mentioned in the interview covered in Hypnosifl's answer (pure speculation, of course, but it seems he's toast, regardless).

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Even the screenwriters have no scenario in mind, see this interview with co-writer Ehren Kruger:

Q: So you’re shifting gears in this film. You’ve got new human characters. But you never actually mention in the film, maybe in the script I don’t know, what happened to Sam. Was there a line of dialogue that got cut where you addressed that?

A: I don’t think it ever made the script. I think we talked about at one point referring to the “Witwicky Incident,” but it never made it, yes.

Q: Do you have any ideas about what he’s doing right now? Because he seemed really eager to be part of the Autobot experience in the previous film, so I wonder how he feels about all this.

A: Well, the reason we ended up not wanting to talk about that too much was that we liked the idea of venturing into this franchise from the perspective of humans on the outside, like the audience, that have just sort of watched these events unfold through the news and through television, and who didn’t know any of the characters or experience the first three things. So they’re coming into this with entirely fresh eyes, without an awareness of things that went on in the previous three films, and well, we liked the purity of that. So we didn’t want [get hung up] with the characters who had been in the previous three.

So until someone decides to do some kind of tie-in media or a new movie that addresses it, I don't think you'll find any kind of remotely "official" answer, only fan speculation.

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    “we liked the idea of venturing into this franchise from the perspective of humans on the outside, like the audience, that have just sort of watched these events unfold through the news and through television, and who didn’t know any of the characters or experience the first three things” — that’s hilarious. Yup, just like the audience, except the ones who saw one or more of the previous three films. Just because we’re trying to forget them doesn’t mean we’ve succeeded. – Paul D. Waite Jul 16 '14 at 9:40
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I am not exactly sure, but following the story line of the movie the following can be said: the Transformers were being hunted by both the humans and the bounty hunter Lockdown. Things had become intense for the Autobots, which means they had to cut ties with their human friends for their own safety. But a dark assumption is they were probably killed by those people who hunted them most, especially that bounty hunter.

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    Hello and welcome to the Stack Exchange. Quick note: "I am not exactly sure" at the beginning of an answer isn't the best sign. It usually indicates an opinion-based or subjective answer. Might I suggest checking out the Tour to get a better idea of how to ask and answer questions here? We're not a typical discussion forum. – Meat Trademark Jun 30 '14 at 10:03
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Perhaps, Bumblebee left Sam so that he'll be safe and not have to be hunted for being the closest ally of the Autobots. And, also, since he loves Sam and will do anything to protect him.

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I believe Sam was killed or arrested, along with all his family and/or associates. If you had noticed, Bumblebee was more aggressive picking fights with another Autobot early into the discovery of the three Autobots... stating:

"I'm gonna kick your ass."

In the past films, Bumblebee seemed more inquisitive and docile, not some bully who picked fights. Maybe Bumblebee's behavior was because of Sam's death or imprisonment, leaving a scar on Bumblebee's mind.

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  • Hi! Welcome to Stack Exchange. This site is not a typical forum: we prefer concrete answers that have some basis in the work itself. Speculation and opinion-based answers are a bad fit for this site. Please check out the Tour (scifi.stackexchange.com/tour) and the other Help information. – KutuluMike Jul 25 '14 at 14:16

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