Studies of inositol polyphosphates in the pancreatic β-cell have led to an exciting synergism between new discoveries regarding their cellular roles and new insights into β-cell function. Because the loss or malfunction of the β-cell is central to diabetes, these studies open the possibility of new pharmacological interventions in a disease that has reached epidemic proportions worldwide. Using the β-cell as our prime but not exclusive example, we examine the inositol polyphosphates in three main groups: 1) inositol 1,4,5-trisphosphate and its influence on Ca(2+) signaling, specifically in a cell in which cytoplasmic-free Ca(2+) concentration is principally increased by plasma membrane standing voltage-gated Ca(2+) channels; 2) higher inositol polyphosphates including a novel second messenger inositol 3,4,5,6-tetrakisphosphate and a regulatory role for inositol hexakisphosphate in β-cell Ca(2+) homeostasis and exo- and endocytosis; and 3) inositol pyrophosphates and their role in β-cell exocytosis, together with the exciting possibility of being novel targets for therapy in diabetes. We conclude with some of the new perspectives that are likely to become apparent in the next few years.