Cells of almost all organisms accumulate organic osmolytes when exposed to hyperosmolality, most often in the form of high salt or urea. In this review, we discuss 1) how the organic osmolytes protect; 2) the identity of osmolytes in Archaea, bacteria, yeast, plants, marine animals, and mammals; 3) the mechanisms by which they are accumulated; 4) sensors of osmolality; 5) the signaling pathways involved; and 6) mutual counteraction by urea and methylamines.