Major Characters! Leads! Main Characters — they're whom the story is about!
There is generally one lead character, The Protagonist. Sometimes there is also a Deuteragonist, the second important character. On rare occasions, there is a "Tritagonist", but it doesn't go any further than that. So there are no "protagonists", just those three and other major characters. These other characters' main character status tends to be defined by how close they are to the lead(s).
Basically, a main character is any character who has a major purpose or role in the plot and/or interacts regularly with main characters. In many series, a name indicates that this character will be a main character, if only for one episode. Without these people, the series would not be the same, and sometimes would be entirely different. If the person has an effect on the plot, but is not affecting it by his or her own merit, this is a Macguffin.
If the story is from first person, then the person speaking will almost always be a main character, though there are exceptions. If the story isn't from first person, then the characters you see around the most will generally be main characters, though, once again, there are exceptions. If a character is in the title, then he or she will be a main character.
See also:
- The Hero (or Heroes)
- Anyone the hero (or The Protagonist) interacts with on a permanent basis
- True Companions
- Sidekicks
- Certain villains (Particularly The Hero's Rogues Gallery)
- The Rival
- Authority Figures (If the hero interacts with this person on a regular basis.)
- Members of The Team they are part of.
- Adaptational Protagonist: A minor or major character becomes The Protagonist in an adaptation or Continuity Reboot.
