Translation of laboratory results to the patient is a critical step in biomedical research and sometimes promising basic science and preclinical results fail to meet the expectations when translated to the clinics. End-to-side (ETS) nerve regeneration is an example of an innovative neurobiological concept, which, after having generated great expectations in experimental and preclinical studies, provided very conflicting results when applied to clinical case series. A number of basic science studies have shown that ETS neurorrhaphy, in fact, is able to induce collateral sprouting from donor nerve's axons, allowing for massive repopulation of the distal nerve stump. Experimental studies have also shown that ETS neurorrhaphy can recover voluntary control of skeletal muscles and that voluntary motor function recovery can be achieved both with agonistic and antagonistic donor nerves, thus widening the potential clinical indications. However, clinical case series reported so far, did not meet these promises and results have been rather conflicting, especially regarding repair of proximally located mixed nerves. In contrast, ETS reconstruction of distal sensory nerve lesions led to a more positive outcome and, most importantly, consistent results among international centers carrying out clinical trials. Concluding, ETS is a promising microsurgical approach for nerve coaptation, based on a convincing and innovative neurobiological concept. However, conflicting clinical results and disagreement among surgeons regarding its employment suggest that this technique should still be considered an ultima ratio, reserved for cases where no other repair technique can be attempted. New data coming from neurobiological research will help further enlarge the clinical indications of ETS nerve reconstruction, explain the different results found in laboratory animals and humans, and contribute to new treatments and rehabilitation strategies aimed at improving the efficacy of nerve regeneration after ETS neurorrhaphy.