Respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3) are two leading causes of lower respiratory illness (LRI) in infants. Many efforts have been directed to develop vaccines against these two viruses. Licensure of new vaccines includes three phases of clinical trials to evaluate safety, immunogenicity, and efficacy. To design an efficacy trial, age-specific incidence rates of suitable clinical endpoints need to be available. In this review, historical data are summarized to estimate the age-specific rates of acute respiratory illness (ARI), LRI, and hospitalization caused by RSV and PIV3 among US children <5 years of age. Nation-wide data are available for hospitalization but not ARI and LRI. Age-specific rates of RSV and PIV3-related ARI or LRI can vary 9-fold or 5-fold, respectively, in different studies conducted in different populations using different clinical and laboratory definitions. The annual medical burden for RSV and PIV3 in children <5 was estimated respectively to be about 4.19 and 3.24 million cases of medically-attended ARI, 2.1 and 1.08 million cases of LRI, and 113 and 29 thousand cases of hospitalization, respectively. The impact of three important variables including age at vaccination, clinical endpoints, and laboratory diagnosis in designing efficacy trials is discussed. A RSV vaccine which is safe and effective in the first six months of life is optimal to reduce the severe disease burden of LRI and hospitalization, however, interference of maternal antibody may reduce vaccine efficacy in this age group. LRI occurs more frequently than hospitalization and may be the most feasible clinical endpoint for designing efficacy trials. Since age-specific rates of RSV and PIV3-related LRI can vary significantly in different populations, collecting age-specific LRI rates in phase 1 and 2 trials to further understand this variability appears warranted.