Biogenic silica (opal) accumulation records were used to trace mechanisms, consequence, and geographic pattern of shifts in the main locus of opal deposition of the World Ocean over the last 15 Myr. Over this time interval, the main opal “sink” seems to have moved from the North Atlantic, to the Pacific, equatorial Pacific, eastern equatorial Pacific, eastern boundary current upwelling systems (California, Namibia, Peru), and finally to the Southern Ocean. The interplay between opal deposition and a series of climatic, tectonic, oceanographic, and biologic events has been analyzed and discussed. These events include the Cenozoic global cooling trend, intensified glaciation in Antarctica, Late Miocene–Early Pliocene biogenic bloom, development of Northern Hemisphere Glaciation (NHG), closing of the Panama Seaway, transition of the climate system from a monopolar- to a bipolar-glaciated world, Mid-Pleistocene Revolution (MPR), nutrient availability, evolution of diatoms and C4 plants, and changes in continental weathering rates. While the observed shifts are mostly traceable to oceanic reorganizations and global climatic evolution, conditions favorable to opal deposition involve the above-mentioned complex mix of processes. For this reason, the interpretation of opal deposition records might not always be straightforward. We, however, believe that it can still provide clear indications of large-scale oceanographic reorganizations in the geological past.