Functional magnetic resonance imaging (fMRI) provides high-resolution, non-invasive estimates of neural activity detected by a blood oxygen level dependent signal by assessing the increase in blood flow to the local vasculature that accompanies neural activity in the brain. fMRI studies with standard hand motor test (index-thumb opposition, ITO, or pinch) in ALS patients show good test-retest reliability and similar amplitude of signals in ALS patients compared with control subjects. Isometric force can be performed with careful control for the force exerted, recruitment of other muscles and motion artefact. The volume (number of voxels above threshold) of sensorimotor and cerebellar cortex activated by ITO is reproducibly larger in ALS patients compared with control subjects. Imagined movements in ALS have been studied, as in amputees, and larger volumes are activated in ALS patients with imagined movements as well, compared with control subjects. fMRI studies in ALS patients evaluating cortical activation during pure somatosensory stimulation cutaneous stimulation of the hand to elicit the palmomental response and cutaneous stimulation of the sole to elicit the plantar response - indicate that ALS patients activate a significantly smaller volume of the contralateral sensorimotor cortex compared to control subjects. No statistically significant difference was seen in other areas, including the ipsilateral cerebellum and the contralateral thalamus. An anterior shift in the volume of cortex activated by these paradigms occurs in ALS patients, with a volume of activation, anteriorly, not activated in control subjects. fMRI studies will complement other clinical neurophysiological and neuroimaging techniques in our future attempts to solve the riddle of ALS and other motor neuron diseases.