Apolipoprotein D (ApoD) is a small glycoprotein of 24 kD, and a member of the lipocalin family. ApoD exerts several intracellular mechanistic roles, especially ligand binding. Some putative ligands are arachidonic acid, progesterone, and tamoxifen. It probably has a binding/reservoir function of these ligands in the cytoplasm. Furthermore, ApoD has features compatible with endosomal trafficking, proteolytic activity and interactions in cellular signal pathways. ApoD inhibits translocation of phosphorylated MAPK into the nucleus. Moreover, ApoD is associated with reduced proliferative activity of cancer cells, and is abundantly raised in senescent cells. In breast cancer, ApoD expression is associated with favourable histology and clinical stage, whereas in adjacent tumour stroma ApoD expression is a marker of adverse prognosis. Oestrogen receptor expression in breast cancer is inversely related to ApoD expression. Therefore, a combined oestrogen receptor positivity/ApoD positivity, could reflect a non-functional oestrogen receptor pathway, and this subset of breast cancer patients does not react to adjuvant tamoxifen treatment. The triangular relationship between oestrogen receptor, tamoxifen and ApoD should be further explored.