Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by loss of spinal and cortical motor neurons, leading to progressive weakness and ultimately, death. Clinically, there appears to be an anatomic focus at disease onset, from which the disease then spreads. Because the focus of initial symptoms and the subsequent direction of spread can vary from patient to patient, disease monitoring is difficult, especially in a clinical trial, in which outcome measures must be identical and able to capture progression of all types. Thus, the search for markers of disease progression is especially important in ALS. Many approaches have been taken, from voluntary strength assessment and functional rating scales to physiological and pathological sampling of affected portions of nervous system. No proposed marker has been demonstrated to meet the desired criteria of biological meaning, sensitivity to disease progression, clear relationship to overall prognosis and survival, and ease of measurement. However, progress is being made in all of these regards.