Motor neuron disease is a devastating progressive neurodegenerative disease, which is irreversible. Delay in the diagnosis is the norm among neurologists and other medical practitioners. It can affect both central and peripheral nervous systems. It also manifests by upper neuron, lower motor neuron signs or a mix of the above two and can affect the bulbar system. Because the disease is primary progressive, it mimics many other neurological deficits at different stages. Unfortunately, there is no one test to confirm the diagnosis at the early stage, typically during the first 12 months. Probably, all the differential diagnosis that reversible and treatable should be ruled out specifically. Patient may be referred to different specialities before being referred to general neurologist. Furthermore, general neurologist may need to refer the patient to motor neuron specialist; motor neuron specialist would like to make sure that he eliminated all the mimics before breaking the bad news with the patient and family that the motor neuron disease is the most probable diagnosis. It is of paramount important that the patient received the diagnosis as early as possible so he/she can benefit from multidisciplinary and interdisciplinary care team and to alleviate his/her symptoms and also to arrange advanced care planning, and assessment of ceiling of the goals of the care. It is of note that currently, patient may benefit from assisting dying if he/she fulfills the criteria. This review aims to include most common mimics and chameleons in the clinical practice and to discuss the diagnostic tools that should be performed for those who has been considered possible motor neuron disease. And to discuss the avenue for assessment by multidisciplinary care team which includes general neurologist, motor neuron specialist, respiratory physician, gastroenterologist, psychologist and psychiatrist, general physician, and allied health.