Commercial high-intensity, short rest (HI/SR) protocols have been anecdotally postured to be extremely demanding. However, limited prior studies have demonstrated HI/SR protocols to produce hyperreactions in metabolic and adrenal function; thus, the purpose of this study was to evaluate the physiological effects of an acute, high-intensity (75% 1-repetition maximum), short rest resistance exercise protocol. Nine trained men (age: 23.5 ± 3.5 years, height: 172.4 ± 4.0 cm, weight: 77.8 ± 8.8 kg) and 9 trained women (age: 22.9 ± 2.0 years, height: 168.4 ± 9.4 cm, weight: 68.5 ± 10.4 kg) participated in the HI/SR protocol, which consisted of a descending pyramid scheme of back squat, bench press, and deadlift, beginning with 10 repetitions of each, then 9, then 8, and so on until 1 repetition on the final set. Significant time effects were observed in lactate (immediate post [IP], +15, +60) and cortisol (IP, +15, +60) response. Significant sex effects were observed in lactate response (IP, +15) but not in cortisol response. Total work was higher in men and influenced magnitude of increase in lactate but not cortisol. No significant sex differences were noted in time to completion, average relative intensity, heart rate response or rating of perceived exertion scores. Highest lactate (IP men: 17.3 mmol·L(-1); IP women: 13.8 mmol·L(-1)) and cortisol (+15 men: 1,860.2 nmol·L(-1); +15 women: 1,831.7 nmol·L(-1)) values were considerably greater than those produced in typical resistance exercise programs, confirming that relative intensity and rest period length are important factors determining magnitude of metabolic and adrenal stress. Practical applications for the coach include cautious implementation of HI/SR protocols, as long-term sequential use may promote overtraining. A gradual reduction in rest interval length with concurrent gradual increase in intensity should be used to minimize potential negative effects such as nonfunctional overreaching.