'Am I taking care of you? I have a thesis to write!' 'My parents are at their house; you visited last--' 'No, no, explain like you're five.'
Megan tells Cueball that she is working on her math thesis. A thesis consists of original research and generally deals with material that is difficult for the uninitiated to understand. Cueball anticipates that it will be difficult to understand, and asks her to "explain it like I'm five". "Explain it like I'm five" is a way of asking for a simpler explanation of some difficult topic, in a way that a five-year-old child would be able to understand. Megan sarcastically (or perhaps not) treats Cueball as if he is an actual 5-year-old without his parents, expressing her concern that a 5-year-old is without any supervision. This is an example of idiomatic language being taken literally, something that Randall has explored in other comics as well, such as 1454: Done, Shake That, and Reverse Euphemisms.
In the title text, Megan feigns concern that she will have to abandon her work to take care of this supposed lost child and takes this role-playing further by refusing to respond to Cueball until he phrases his comments as a 5-year-old would.
The common expression "Explain it like I'm five" is inspired by a line by Groucho Marx in his movie Duck Soup. "Why a four-year-old child could understand this report! Run out and find me a four-year-old child, I can't make head or tail of it."[1]