The efficiency of protein utilization for growth in preruminant calves is decreasing with increasing body weight. In contrast to calves weighing less than 100 kg of body weight, heavy preruminant calves do not respond in protein retention to an increased intake of indispensable amino acids in dose-response studies. The marginal efficiency of protein utilization is low compared with pigs and milk-fed lambs at a similar stage of maturity. A reductionist approach was taken to perceive the potential mechanisms for the low protein utilization in preruminant calves. Neither an imbalance in the dietary protein to energy ratio nor a single limiting indispensable amino acid was responsible for the low efficiency. Also, amino acids were not specifically used to detoxify ammonia. Alternative hypotheses to explain the low efficiency are discussed and result in (i) a reduced post-absorptive supply of amino acids: e.g. by fermentation of milk in the (premature) rumen or preferential amino acid utilization by specific tissues; or (ii) a reduced post-absorptive amino acid utilization: e.g. by decreased insulin sensitivity, utilization of amino acids for gluconeogenesis or an asynchronous nutrient supply. In conclusion, several mechanisms for the low efficiency of protein utilization in heavy preruminant calves were excluded. Other physiological processes which are potentially involved remain to be studied, because the large potential for improving protein utilization in heavy preruminant calves asks for further exploration of their amino acid metabolism.