With the acceleration in our understanding of ALS and the related motor neuron disease has come even greater challenges in reconciling all of the proposed pathogenic mechanisms and how this will translate into impactful treatments. Fundamental issues such as diagnostic definition(s) of the disease spectrum, relevant biomarkers, the impact of multiple novel genetic mutations and the significant effect of symptomatic treatments on disease progression are all areas of active investigation. In this review, we will focus on these key issues and highlight the challenges that confront both clinicians and basic science researchers.