Amyotrophic lateral sclerosis (ALS) is an incurable disease, caused by the loss of the upper and lower motor neurons. The lack of therapeutic progress is mainly due to the insufficient understanding of complexity and heterogeneity underlying the pathogenic mechanisms of ALS. Recently, we analyzed whole-genome expression profiles of motor cortex of sporadic ALS patients, classifying them into two subgroups characterized by differentially expressed genes and pathways. Some of the deregulated genes encode proteins, which are primary targets of drugs currently in preclinical or clinical studies for several clinical conditions, including neurodegenerative diseases. In this review, we discuss in-depth the potential role of these candidate targets in ALS pathogenesis, highlighting their possible relevance for personalized ALS treatments.