Genetic instability was postulated to be essential for tumor development almost three decades ago, and yet its exact nature in and relationship with cancer continue to be ill-understood and hotly debated subjects. In this article, we review and discuss current knowledge and thinking about the existence, characteristics, reasons for and mechanisms of genetic instability in human cancers, as well as how its study can help us better understand and fight cancer. Particular emphasis is given to chromosomal instability, the most common and least understood of the types of genetic instability found in human tumors.