This review describes processes for the distribution of K+ ([K+]) and lactate concentrations ([Lac-]) that are released from contracting muscle at high rates during high-intensity exercise. This results in increased interstitial and venous [K+] and [Lac-] in contracting muscle. Large and rapid increases in plasma [K+] and [Lac-] result in the transport of these ions into red blood cells (RBCs). These ions are distributed to noncontracting tissues within both the plasma and RBC compartments of blood. The extraction of K+ and Lac- from the circulation by noncontracting tissue serves to markedly attenuate exercise-induced increases in plasma [K+] and [Lac-]. This apparent regulation of the plasma compartment by noncontracting tissues helps to maintain favorable concentration gradients for the net movement of [K+] and [Lac-] into the venous side of the microcirculation from interstitial fluids of contracting muscle. This provides conditions that 1) reduce the increase in interstitial [K+], thereby decreasing the magnitude and rate of sarcolemmal depolarization, and 2) favor the sarcolemmal transport of Lac- from within contracting muscle cells, thereby regulating intracellular osmolality and H+ concentration. On cessation of exercise, net K+ uptake by recovering muscle is rapid, with 90–95% recovery of intracellular [K+] within 3.5 min, indicating a very high rate of Na+-K+ pump activity. The K+ extracted by noncontracting tissues during exercise may be slowly released during recovery. During the initial minutes of recovery, recovering muscle continues to release Lac- into the circulation, and noncontracting tissues continue to extract Lac- for up to 30 min. The uptake of Lac- by noncontracting tissues results in elevated intracellular [Lac-]. There is no evidence that Lac- extracted by noncontracting tissues is subsequently released; it is probably metabolized within these cells. We conclude that the uptake of K+ and Lac- by RBCs and noncontracting tissues regulates ion homeostasis within plasma and the interstitial and intracellular compartments of contracting muscle. The regulatory processes help to maintain the function of active muscles by delaying the onset of fatigue during exercise and to restore homeostasis during recovery.