The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) is considered a "candidate" tumor suppressor gene. This hypothesis has been provoked by the identification of loss of heterozygosity (LOH) at the M6P/IGF2R locus on chromosome 6q26 in breast and liver cancer, accompanied by point mutations in the remaining allele. Somatic mutations in coding region microsatellites have also been described in replication error positive (RER+) tumors of the gastrointestinal tract, endometrium and brain. These genetic data are compelling, but a tumor suppressor gene candidate has to meet functional as well as genetic criteria. This review weighs the evidence and discusses the observations that are necessary to promote M6P/IGF2R from candidate to bona fide tumor suppressor gene.