Heart failure is the leading cause of hospitalizations and readmissions. Guideline-directed medical therapy is the cornerstone to improving outcomes, but less than 20% of patients with heart failure marked by reduced ejection fraction receive target doses. This report reviews the neurohormonal cascade that occurs in heart failure and the role of guideline-directed medical therapy based on the results of landmark trials. In addition, evidence-based strategies to up-titrate medications are described. Nurse practitioners are in an optimal situation to titrate guideline therapy with frequent follow-up and monitoring.