ALS currently remains a challenge despite many efforts in performing successful clinical trials and formulating therapeutic solutions. By learning from current failures and striving for success, scientists and clinicians are checking every possibility to search for missing hints and efficacious treatments. Because the disease is very complex and heterogeneous and, moreover, targeting not only motor neurons but also several different cell types including muscle, glial, and immune cells, the right answer to ALS is conceivably a multidrug strategy or the use of broad-spectrum molecules. The aim of the present work is to gather evidence about novel perspectives on ALS pathogenesis and to present recent and innovative paradigms for therapy. In particular, we describe how an old molecule possessing immunomodulatory and neuroprotective functions beyond its recognized effects on allergy, histamine, might have a renewed and far-reaching momentum in ALS.