Abstract: Most diploid cells proliferate by proceeding through the canonical G1 (DNA pre-synthesis), S (DNA synthesis), G2 (DNA postsynthesis), and M(mitosis) phases of the cell cycle. However, there is another type of cell cycle that occurs frequently in both plants and animals, known as endoreplication. Endoreplication consists of alternating periods of G and S phases without cytokinesis, which results in polyploidy. It is indispensable for normal development, organ formation, and wound healing in humans. In recent years, considerable attention has been paid to delineating the connections of endoreplication with tumorigenesis and tumor progression. Here, we review the role of endoreplication in normal human development and discuss its possible role in tumor development and the underlying molecular mechanisms.