BACKGROUND: High resistance training enhances muscular strength, and recent work has suggested an important role for metabolite accumulation in this process. OBJECTIVE: To investigate the role of fatigue and metabolite accumulation in strength gains by comparing highly fatiguing and non-fatiguing isotonic training protocols. METHODS: Twenty three healthy adults (18-29 years of age; eight women) were assigned to either a high fatigue protocol (HF: four sets of 10 repetitions with 30 seconds rest between sets) to maximise metabolic stress or a low fatigue protocol (LF: 40 repetitions with 30 seconds between each repetition) to minimise changes. Subjects lifted on average 73% of their 1 repetition maximum through the full range of knee extension with both legs, three times a week. Quadriceps isometric strength of each leg was measured at a knee joint angle of 1.57 rad (90 degrees ), and a Cybex 340 isokinetic dynamometer was used to measure the angle-torque and torque-velocity relations of the non-dominant leg. RESULTS: At the mid-point of the training, the HF group had 50% greater gains in isometric strength, although this was not significant (4.5 weeks: HF, 13.3 (4.4)%; LF, 8.9 (3.6)%). This rate of increase was not sustained by the HF group, and after nine weeks of training all the strength measurements showed similar improvements for both groups (isometric strength: HF, 18.2 (3.9)%; LF, 14.5 (4.0)%). The strength gains were limited to the longer muscle lengths despite training over the full range of movement. CONCLUSIONS: Fatigue and metabolite accumulation do not appear to be critical stimuli for strength gain, and resistance training can be effective without the severe discomfort and acute physical effort associated with fatiguing contractions.