Whilst our understanding of the etiology of ALS has increased significantly in recent years, major gaps in our knowledge remain. In this review, we address several unanswered questions regarding the unique susceptibility of specific types of MNs in ALS: Why does neurodegeneration spread throughout specific neural networks? How can ubiquitously expressed genes be selectively toxic to MNs? Why are some MN subtypes more vulnerable to degeneration than others? We also discuss the role of the neuronal network and the specific cellular microenvironment in driving cell-to-cell disease progression, plus the importance of genetics in influencing susceptibility of specific neuronal subpopulations. Finally, we discuss the role of aging as a potential risk factor for the susceptibility of specific MN subtypes. A thorough comprehension of why specific cell types degenerate is imperative to our understanding of ALS because it provides important clues as to what initiates neurodegeneration, and how this knowledge may be harnessed therapeutically.