Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous disease in terms of progression rate and survival. This is probably one of the reasons for the failure of many clinical trials and the lack of effective therapies. Similar variability is also seen in SOD1G93A mouse models based on their genetic background. For example, when the SOD1G93A transgene is expressed in C57BL6 background the phenotype is mild with slower disease progression than in the 129Sv mice expressing the same amount of transgene but showing faster progression and shorter lifespan. This review summarizes and discusses data obtained from the analysis of these two mouse models under different aspects such as the motor phenotype, neuropathological alterations in the central nervous system (CNS) and peripheral nervous system (PNS) and the motor neuron autonomous and non-cell autonomous mechanisms with the aim of finding elements to explain the different rates of disease progression. We also discuss the identification of promising prognostic biomarkers by comparative analysis of the two ALS mouse models. This analysis might possibly suggest new strategies for effective therapeutic intervention in ALS to slow significantly or even block the course of the disease.