The activation of a telomere maintenance mechanism (TMM) is indispensable for cellular immortalization, a hallmark of human cancer. Although most human cancers use telomerase as their TMM, some use an alternative lengthening of telomeres (ALT) mechanism. The latter especially include specific subtypes of soft tissue sarcomas where ALT occurs most often in tumors with complex karyotypes, astrocytic brain tumors and osteosarcomas. The prognostic significance of ALT varies according to the type of tumor. Some ALT cells have atypical features, suggesting the possibility that there is more than one ALT mechanism. ALT cells are characterized by instability at a specific minisatellite locus (although they are stable at microsatellite loci) and by high rates of telomeric recombinational exchange. We propose a revised model whereby unequal telomeric exchange and asymmetrical chromosome segregation could result in telomere length maintenance in a cell population. In at least some ALT cells, telomere maintenance requires the integrity of the MRN (MRE11-RAD50-NBS1) recombination complex and is efficiently repressed by its sequestration. Microsatellite instability (MSI) often results in disruption of MRN, so ALT may usually be incompatible with MSI. We suggest that ALT in human tumors is a dysregulated version of an aspect of normal mammalian telomere homeostasis, which may be a vestige of the TMM used by ancient eukaryotes. Understanding the molecular basis of ALT has important implications for the diagnosis and treatment of tumors that use this TMM.