Fatigue, despite being the most common and distressing symptom in cancer, is often unrelieved because of numerous patient, provider, and system barriers. The overall purpose of this 5-year prospective clinical trial is to translate the NCCN Cancer-Related Fatigue Clinical Practice Guidelines in Oncology and NCCN Adult Cancer Pain Clinical Practice Guidelines in Oncology into practice and develop a translational interventional model that can be replicated across settings. This article focuses on one NCCN member institution's experience related to the first phase of the NCCN Cancer-Related Fatigue Guidelines implementation, describing usual care compared with evidence-based guidelines. Phase 1 of this 3-phased clinical trial compared the usual care of fatigue with that administered according to the NCCN guidelines. Eligibility criteria included age 18 years or older; English-speaking; diagnosed with breast, lung, colon, or prostate cancer; and fatigue and/or pain ratings of 4 or more on a 0 to 10 screening scale. Research nurses screened all available subjects in a cancer center medical oncology clinic to identify those meeting these criteria. Instruments included the Piper Fatigue Scale, a Fatigue Barriers Scale, a Fatigue Knowledge Scale, and a Fatigue Chart Audit Tool. Descriptive and inferential statistics were used in data analysis. At baseline, 45 patients had fatigue only (≥ 4) and 24 had both fatigue and pain (≥ 4). This combined sample (N = 69) was predominantly Caucasian (65%), female (63%), an average of 60 years old, diagnosed with stage 3 or 4 breast cancer, and undergoing treatment (82%). The most common barriers noted were patients' belief that physicians would introduce the subject of fatigue if it was important (patient barrier); lack of fatigue documentation (professional barrier); and lack of supportive care referrals (system barrier). Findings showed several patient, professional, and system barriers that distinguish usual care from that recommended by the NCCN Cancer-Related Fatigue Guidelines. Phase 2, the intervention model, is designed to decrease these barriers and improve patient outcomes over time, and is in progress.