Recent studies in the central equatorial Pacific allow a comprehensive assessment of phytoplankton regulation in a high-nutrient, low-chlorophyll (HNLC) ecosystem. Elemental iron enters the euphotic zone principally via upwelling and is present at concentrations (≤30 pM) well below the estimated half-saturation constant (120 pM) for the large cells that bloom with iron enrichment. In addition, the meridional trend in quantum yield of photosynthesis suggests that even the dominant small phytoplankton are held below their physiological potential by iron deficiency. Grazing by microzooplankton dominates phytoplankton losses, accounting for virtually all of the measured phytoplankton production during El Niño conditions and ∼66% during normal upwelling conditions, with mesozooplankton grazing and lateral advection closing the balance. Nitrate uptake is strongly correlated with the pigment biomass of diatoms, which increase in relative abundance during normal upwelling conditions. Nonetheless, the f-ratio remains low (0.07–0.12) under all conditions. Iron budgets are consistent with the notions that new production is determined by the rate of new iron input to the system while total production depends on efficient iron recycling by grazers. Although the limiting substrates differ, the interactions of resource limitation and grazing in HNLC regions are conceptually similar to the generally accepted view for oligotrophic subtropical regions. In both systems, small dominant phytoplankton grow at rapid, but usually less than physiologically maximal, rates; they are cropped to low stable abundances by microzooplankton; and their sustained high rates of growth depend on the remineralized by-products of grazing.