Amyotrophic lateral sclerosis (ALS) is one of the most common neuromuscular diseases. It is devastating and fatal, causing progressive paralysis of all voluntary muscles and eventually death, while sparing cognitive functions. A pathological hallmark of ALS is neuroinflammation mediated by non-neuronal cells in the nervous system, such as microglia and astrocytes that accelerate the disease progression. Scientists have neither found a unique key mechanism, nor an effective treatment against ALS, supposedly because it is a multi-factorial and multi-systemic disease. Extracellular purines and pyrimidines are widespread and powerful physiopathological molecules, signalling to most cell types and directing cell-to-cell communication networks. They are instrumental for instance for neurotransmission, muscle contraction and immune surveillance. Recent work has reported the crucial involvement of purinergic pathways in many neurodegenerative and neuroinflammatory diseases, comprising ALS. Especially P2 receptors for ATP, P1 receptors for adenosine, and nucleotide transporters were found to be modulated in ALS cells and tissues, playing a potential role in the disease. Given the composite cellular cross-talk occurring during ALS and the established action of extracellular purines/pyrimidines as neuron-to-glia alarm signal in the nervous system, a mutual query in these two fields should now be whether, how and when purinergic would meet ALS. In this review, we will highlight the early cellular and molecular purinergic cross-talk that participates to ALS etiopathology, with the conviction that better understanding of purinergic dynamics might provide original research perspectives, stimulate alternative disease modelling, and the design and testing of more powerful targeted therapeutics against this relentlessly progressive disorder.