Although misdiagnosis of amyotrophic lateral sclerosis (ALS) is rare, it may be more difficult to make a diagnosis in some groups of patients than in others. If a patient presents in the later stages of the disease, only a small number of alternative diagnoses need to be considered. These include spinal muscular atrophies of adult onset, inclusion body myositis and motor neuropathies with conduction block. The latter group in particular may present a serious diagnostic problem, as several groups have recently reported patients suffering from lower motor neuron syndrome without detectable conduction block, who responded unexpectedly to treatment with immunoglobulins. As recent laboratory results suggest that a lengthy pre-clinical period may precede clinical ALS, there is increased pressure for clinicians to make an early diagnosis so that the maximum effect can be achieved from neuroprotective drugs. Thus, diseases such as distal motor amyotrophies, pressure palsies of motor branches of hand nerves, and cervical myelopathies, which can be differentiated mainly by their time-course, may be relevant in the differential diagnosis of ALS in some patients. During recent years, a few patients have been seen in our clinic who presented with pure motor deficits but later developed a more complex pattern of vulnerability suggestive of multisystem degeneration. The existence of patients with a disease that borders the spectrum of motor neuron diseases cannot be disputed. These patients include those carrying the Huntington mutation and those suffering from Guam and New Guinea disease ('ALS/PD'). From our experience, however, these 'difficult' diagnoses represent less than 10% of the patients seen in our clinic.