The two daughter cells that result from each and every cell division receive an identical set of chromosomes. This is accomplished by pulling each copy of a pair of duplicated sister chromatids to opposite poles during mitosis. Inaccuracies in this process lead to aneuploidy, which is a major cause of birth defects and can facilitate the rise of malignancies. Such inaccuracies are prevented in normal cells by the mitotic checkpoint (also known as the spindle assembly checkpoint) that halts cell cycle progression in mitosis when as little as a single chromosome is not properly attached to the mitotic spindle. This review focuses on molecular aspects of mitotic checkpoint signaling in mammals, including sensing improper attachments and transducing this information to the cell-cycle machinery.