Since the beginning, Clusterin (CLU) was revealed not as simple to study, and certainly not a single protein. The growing research interest on CLU soon produced many contributions by independent laboratories working in different systems. Thus, many different names or acronyms have been given to CLU in the early years after its discovery. Now, a general consensus recommend the name Clusterin and the abbreviation CLU. CLU was first described as a glycoprotein found nearly ubiquitous in tissues and body fluids. This early knowledge is mostly related to the secretory form of CLU (sCLU), which is exported from the cell and released in secretions acting as an extracellular chaperone. But CLU can also enter the nucleus. The detection of nCLU (nuclear CLU), which is usually associated to cell death, is now emerging as a very important event making this issue even more complex. This may explain why CLU is still often described as an “enigmatic” protein. The use of the term “enigmatic” is a clear indication that too many aspects related to the biological function(s) of CLU and its possible role in pathogenesis have been obscure, or very difficult to interpret, for long time. Contradictory findings on CLU are also present in the literature, sometimes due to technical biases or alternative interpretation of the same result. The aim of the book is ambitious: through a careful review of old data, in the light of novel information and up to date methods and hypotheses, we will try to simplify the picture for the reader and bring more light in a field still perceived to be too obscure to fully appreciate its importance and potential implementation in the clinical setting. This introduction will provide a brief general history and a critical view of the discovery of CLU with the aim to underline what is new in the field and what is now obsolete. In the rest of the book, conclusions and “take home messages” will also be provided to the reader particularly focusing on possible clinical implementations and how all this knowledge will very likely bring novelty in the fight against cancer.