Effective clinical trials in neuromuscular research require accurate and sensitive methods to quantitate disease progression. The purpose of this study was to concurrently compare manual muscle testing (MMT), maximal voluntary isometric contraction (MVIC), and a functional scale (the ALS Score). Twenty patients with ALS were tested ten times at monthly intervals using each of the three methods. High inter-rater reliability for each of the three methods was demonstrated. All three methods demonstrated a decline over the testing period. However, MMT and the ALS Score were less sensitive to early change. A wide variation of percent of normal MVIC was demonstrated within each MMT grade and extensive overlap between MMT grades was observed. MVIC is the method of choice in studying patients in the early stages of ALS and in studies conducted over a short period of time.