We have compared the effects of insulin with those of elevated external K+ concentration ([K+]o) on sugar uptake and protein synthesis by frog skeletal muscle. When [K+]o was between 0.5 and 15 mM there were no effects on uptake; however, when 20 mM was used a significant increase was observed. Further increases in [K+]o caused larger stimulations of uptake. The stimulation persisted for 2.5 h after washing the high [K+]o. The stimulations caused by both insulin and high K+ were markedly inhibited by cytochalasin B. Dantrolene nearly abolished the response to high K+, whereas it had only minor effects on the resting sugar uptake and on the stimulations caused by either insulin or epinephrine. These results suggest that while both insulin and high K+ activate the cytochalasin-sensitive transport system of sugar transport, each agent must act through a different pathway, because only the effects of high K+ were dantrolene sensitive. The effect of dantrolene suggests that the enhancement of sugar transport caused by high K+ is due to an increase of cytoplasmic Ca2+. In contrast to insulin, high K+ did not modify the rate of protein synthesis.