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Polycomb Group (PcG) genes are known to encode a large chromatin-associated family of proteins which are involved in genomic regulation of many cellular processes. Su(z)12 is a key component in PcG silencing. It is needed for three levels of methylation of histone 3 lysine 27 in vivo in Drosophila. Here, we report that Su(z)12 may exist in different isoforms and that these isoforms are spatially and temporally regulated. The biological function of the Su(z)12-A and -B isoforms seems to be very different. For instance the transgenic Su(z)12-B and the human homolog SUZ12, but not Su(z)12-A, rescue Su(z)12 mutants. Furthermore, transgenic flies over-expressing Su(z)12-B show typical homeotic transformation phenotypes, while over-expression of Su(z)12-A does not. However, the two isoforms appears to be able to substitute for each other in some aspects. During larval and pupal stages, Su(z)12-A seems to play the main role.