Clusterin/Apolipoprotein J (CLU) is a secreted heterodimeric glycoprotein. We recently cloned CLU as a gene induced during cellular senescence and showed that apart from being up-regulated following cell exposure to various types of stress it also accumulates in the human serum during several age related diseases. Moreover, CLU is reportedly up regulated during tumorigenesis, as well as during cell injury or death. Nevertheless, despite extensive effort CLU function remains largely elusive. We are using as a model to study CLU three human osteosarcoma (OS) cell lines, namely Sa OS, KH OS and U-2 OS cells, that express distinct endogenous CLU protein levels and accumulate the CLU protein to a different extend following apoptosis induction by the chemotherapeutic drug doxorubicin (DXR). We initially applied siRNA-mediated specific knock down of the CLU protein in the OS cells. The synthetic RNA duplexes used apart from effectively silencing CLU gene expression could also inhibit the observed CLU protein up-regulation during DXR-mediated apoptosis. CLU knockdown resulted in all cell lines in significant growth retardation, higher rates of spontaneous endogenous apoptosis and increased sensitisation to DXR-mediated apoptosis. Surprisingly, although low levels of CLU stable over expression conferred cytoprotection accumulation by stable over expression of high CLU protein intracellular levels promoted apoptosis at high DXR doses. In summary, our data provide evidence that although CLU functions mainly cytoprotectively it may becomes highly cytotoxic when accumulates in high intracellular amounts. This chimerical function resembles other molecules, (e.g. p53) that can either promote or inhibit apoptosis depending on their intracellular levels.