Protein substitutes are an essential component in the management of phenylketonuria. A series of studies at Birmingham Children's Hospital have investigated their optimal dosage, timing and practical administration as well as the efficacy and tolerance of novel protein substitutes. The key findings are as follows. (1). Lower dosages of protein substitute (1.2 g/kg per day of protein equivalent) adversely affect blood phenylalanine control in children aged 1-10 years. (2). There is wide variability in 24 h blood phenylalanine concentrations. (3). Adjusting protein substitute timing during daytime does not reduce blood phenylalanine variability. (4). Repeated 4 h administration of protein substitute throughout 24 h markedly reduces phenylalanine variability and leads to lower phenylalanine concentrations. (5). The new, concentrated, low-volume protein substitutes and amino acid tablet preparations are efficacious and well tolerated by patients. (6). Administration of protein substitute as a gel or paste has reduced difficulties with administration of protein substitute in children. These findings are important in rationalizing treatment strategies, improving patient compliance and overall in improving blood phenylalanine control.