Emily Elizabeth is struggling to fit in at home and in school when she meets Clifford, a tiny red puppy who is destined to become her best friend. But when Clifford undergoes a magical growth spurt overnight, he attracts the attention of a genetics company looking for a way to supersize animals. With the help of her Uncle Casey, the people in her neighborhood, and some new friends made along the way, Emily Elizabeth and Clifford have to go on the run across New York City!