Our objective has been a review of the recent data available in reference to the split hand clinical sign in amyotrophic lateral sclerosis (ALS) and its novel electrophysiological counterpart the split hand index (SHI). We have conducted an extensive search on the subject literature published over the last ten years, correlating it with our own experience. ALS patients frequently present asymmetric wasting of the hand muscles, with the abductor pollicis brevis (APB) and first dorsal interosseous (FDI) more severely affected and sparing of the medial hand. The phenomenon has been called Split Hand Syndrome and is a specific clinical marker for early ALS. More recently, the SHI has been included in the electromyographical examination, being derived from the compound muscle action potentials (CMAP) of APB, FDI and abductor digit minim (ADM). SHI has been shown to have a good sensitivity and a specificity in differentiating ALS from mimicking disorders and it also correlates with the disease progression. We conclude that the split hand sign and its electrophysiological counterpart are useful instruments for the neurologist in making an early ALS diagnosis, especially when confounding factors are present.