The objective of this study was to use a model relating lysine (Lys) intake and weight gain in calves to identify optimal alternative protein sources for use in calf diets to minimize cost of gain (COG). A nonlinear optimization was used to minimize COG by adjusting milk replacer formulation subject to biological and practical constraints. The optimizer balanced milk replacer formulas for calves on a weekly basis from wk 1 through 8 of age. Body weight was diet dependent and updated weekly. Energy and mineral requirements of calves were calculated weekly following NRC (2001). Biological, practical and economic constraints were used to define the feasible set of ingredient combinations. Daily Lys intake was used to estimate nitrogen retention for each age group and change in body protein content was tracked. A literature search of calf slaughter balance studies was used to derive allometric equations relating body protein content to body fat, water and ash content. These functions were differentiated and change in body weight was calculated as the sum of the changes in body protein, fat, water and ash. Diet cost was estimated from current ingredient prices and dietary inclusion rates. Sensitivity of the model outputs to feedstuff Lys, protein content and digestibility was performed by taking 10,000 random draws of these parameters from normal distributions, running the growth model and calculating final weight and COG. Standard deviations in feedstuff Lys, protein content and digestibility were sourced from the National Animal Nutrition Program website. The optimal diet relied on a milk protein base with steadily increased inclusion of wheat gluten as animals aged. Blood meal and meat meal were also identified as key alternative protein sources. Model solutions were very robust. After 8 weeks calves weighed 87.8 ± 0.1 kg and COG was $0.358/kg ± $0.001/kg. Protein content and digestibility and Lys significantly (P < 0.001) affected COG and BW and protein digestibility was quantitatively the most important parameter to estimate.