Motor neuron diseases (MNDs) are a debilitating subset of diseases, which result in progressive neuronal destruction and eventual loss of voluntary muscular function. These entities are often challenging to distinguish and accurately diagnose given overlapping clinical pictures and overall rarity. This group of diseases has a high morbidity and mortality rate overall and delineating each type of disease can help guide appropriate clinical management and improve quality of life for patients. Of all MNDs, amyotrophic lateral sclerosis (ALS) is by far the most common comprising 80%-90% of cases. However, other mimics and variants of ALS can appear similar both clinically and radiographically. In this review, we delve into the epidemiological, physiological, neuroimaging, and prognostic characteristics and management of ALS and its most common MND mimics/variants. In doing so, we hope to improve accuracy in diagnosis and potential management for this rare group of diseases.