Homology-dependent gene silencing can be observed when multiple copies of a transgene or a transgene with homology to an endogenous plant gene are present in a plant genome. Both linked and unlinked copies can be affected. Two general types of silencing, involving either transcriptional inactivation or a post-transcriptional process, have been identified. The former has been associated with homology in promoter regions, increased methylation, and meiotically heritable reductions in gene activity, while the latter requires homology in the protein coding region and does not usually lead to heritable alterations in either methylation or gene expression. Different silencing and target loci that exemplify each of these silencing effects will be described. Comparisons will be made with nontransgenic plant and fungal systems that exhibit similar behavior. The possibility that homology-dependent interactions between noncoding repeats play a role in regulating eukaryotic gene expression by silencing large portions of genomes will be discussed.