Red blood cell (RBC) storage is a logistic necessity. However, storage is accompanied by progressive accumulation of morphological and biochemical RBC alterations, which may ultimately impact the quality of the blood product and transfusion efficacy. The progression and severity of the storage lesion are impacted by multifactorial processes, including processing, storage additives and donor biology. Understanding how blood donor, component manufacturing, and recipient characteristics interface to impact patient outcomes is highly interesting in transfusion medicine. Accumulating molecular and clinical evidence suggests a potential impact of donor factors such as sex, age, ethnicity, and genetic variants on stored RBCs' metabolic and hemolytic properties. We will thus discuss recent clinical and molecular evidence on the impact of donors’ social behaviors (e.g., smoking, moderate alcohol consumption, diet, and exercise) on the quality of donated components and outcomes in transfusion recipients. We will review the importance of well-designed pilot studies in evaluating blood donor social behaviors, including ancillary laboratory methods to confirm donor questionnaire responses. The role of confirmatory studies utilizing big data (large databases that link donors to components and recipients) will be explored to emphasize the importance of a multivariable approach in studying recipient transfusion outcomes. Lastly, we will explore how the metabolic age of blood components is influenced by donor social behaviors, as gleaned by high throughput omics technologies. We will show how Omics approaches can directly quantify metabolic markers of nicotine, alcohol, caffeine, drug (prescription/off-the-counter), or other dietary/xenometabolite exposure and relate these measurements to the progression and severity of the storage lesion.