Given the limited knowledge surrounding calf-rearing systems a series of studies were developed to address some of the aspects regarding colostrum and whole milk (non-saleable or hospital milk) physical process (Chapter 1), supplementation of trace minerals (Chapter 2), non-antimicrobial alternatives to prevent and control neonatal calf diarrhea (Chapter 3 and 4), to evaluate antimicrobial metaphylactic interventions in high-risk group of animals (Chapter 5), and finally to determine if pulmonary lesions in dairy heifers at weaning were associated with survival and reproductive performance (Chapter 6). Alternatives to heat-treatment of colostrum and non-saleable milk using ultraviolet light herein explored showed decreased levels of immunoglobulins in colostrum. Ultraviolet light and heat treatment decreased microorganism contamination. However, colostrum and non-saleable milk treatments were not associated with calf survivability, incidence of diseases (diarrhea and pneumonia), and average daily weight gain during the pre-weaning period. Injectable trace minerals supplementation improved leukocyte function and oxidative stress levels in dairy calves. However, these benefits did not translate to improved growth performance and health status for dairy calves in the first 60 days of life. Enteric-coated crofelemer extract, a natural-product with anti-secretory properties exhibited a significant increase in fecal dry matter in diarrheic neonatal calves in a challenge study. Furthermore, when the natural extract was administered prophylactically for the first two weeks of life, milk fed calves experienced significantly fewer events of diarrhea and reduced use of fluid therapy when compared to non-treated calves. A metaphylactic intervention using synthetic long acting macrolide significantly decreased the combined incidence of respiratory disease and otitis in high-risk group-housed replacement heifers during the pre-weaning period. Finally, nulliparous heifers suffered consequences from lung consolidation detected at weaning through a decrease in reproductive performance and an increase in culling risk. There are many important aspects on prevention and treatment of diseases affecting replacement dairy heifers. Strategically, different approaches can be used to improve replacement heifers’ health and performance.