Large-conductance Ca2+- and voltage-activated K+ (BKCa, MaxiK, or Slo1) channels are expressed in almost every tissue in our body and participate in many critical functions such as neuronal excitability, vascular tone regulation, and neurotransmitter release. The functional versatility of BKCa channels owes in part to the availability of a spectacularly wide array of biological modulators of the channel function. In this presentation, we focus on modulation of BKCa channels by small endogenous lipids, emphasizing their molecular mechanisms and potential clinical significance. The mechanistic information is expected to contribute to our understanding of the physiological and pathophysiological roles of BKCa channels.