Motor neurons are unique cells compared to other neurons. They are large cells, with extraordinarily long axons, and very high energetic requirements, which may render them uniquely susceptible to degeneration in ALS. Remarkably, however, not all MNs are equally affected, and there are marked differences in vulnerabilities between MN subtypes, even within the same motor unit. The resistant MNs possess distinct morphological and functional characteristics, as well as different gene expression profiles, compared to the more vulnerable groups (Figure 4). Importantly, the oculomotor neurons continue to function, even in the late stages of ALS when the vulnerable spinal and other MNs are significantly depleted. These oculomotor neurons are anatomically and functionally very different from all other motor units: they are much smaller, and their function involves sensing rather than movement, hence different circuits are involved. In contrast, spinal MNs are more prone to hyperexcitation and they express high levels of AMPA receptors, they are more prone to develop ER stress, and they do not buffer Ca2+ as well as the more resistant MN types. These properties may confer unique sensitivity to neurodegeneration in ALS. Interestingly, even within spinal MNs, there are distinct differences in vulnerability, because FF-MNs degenerate first, followed by FR-MNs, and the more resistant S-MNs degenerate later. Similarly, these cells also display differences in excitability and ER stress.