Have you ever gotten a critique that said, "I'm not sure I care about this story"? It could be the most frightening comment out there. Not "the setting needs work" not "the characters aren't coming together" - no, seemingly everything is working but the reader just doesn't care. This question is a complete deal-breaker on a story, but very often, a critiquer who wants to ask the question doesn't dare, because he or she knows how terrible it will sound to the person being critiqued.
That's why you need to be asking yourself.
There are two optimal times when one can ask this question. The first time is when you're designing your opening hook. After all, the hook is going to have a much harder time "hooking" if the reader doesn't care! The next time is when you've finished a draft and are going back to make sure it's all working as planned.
So what is it that makes a reader care?
This is a tricky question, and not everyone will answer entirely the same way. However, the best place to look is at the protagonist and their goals, and what will happen if those goals are not met. Typically I'd recommend doing the check by asking three (pairs of) questions:
1. Is this a protagonist I feel like following? Why?
2. What is the protagonist's goal? Does it seem worthwhile?
3. What will happen if this goal is not achieved? Is it bad?
Question 1 is really about how relatable your protagonist is. Likeability can be a plus, but if that person shares some general concerns with the reader, that can make them more relatable. Also if the protagonist has very unusual skills or other features that make them fascinating, that is a great help.
Question 2 is a bit sneaky. Occasionally I'll have trouble with it - not because my protagonist has no goal, but because my sense of the protagonist's goal might not make it out of my head onto the page. If the protagonist doesn't want anything, it's hard to get on their side. It's also hard to see where the story might be going. So make sure that you're checking to make sure your lead character has a direction to go.
Question 3 is about stakes. As Janice Hardy would say, if a character has a choice, and both are fine so it really doesn't seem to matter which one he/she picks, then why should we care? If my character's goal is to eat the ice cream, that's not necessarily worth caring about. If my character's goal is to keep from starving, that's a bit more meaningful. Or if my character's goal is to eat the ice cream without permission and thus pull a prank that will make him/her the god of all kids at the school, risking getting in serious trouble with the principal, then that could work too.
In my experience, this is the comment that hurts most from a critiquer. But it is also one of the most critical. I therefore encourage you all to ask it of yourselves before you have to hear it asked by someone else!