The inbuilt biological machinery from molecules to systems is responsible for a wide variety of complex body functions and controls that are often mimicked or disrupted by drugs among other xenobiotics. This chapter focuses on the function and dysfunction of biological systems especially cardiovascular and gastrointestinal systems (from healthy to diseased state) to provide a mechanistic background for drug and nondrug entities interactions (DNIs) with the overall impact on drug absorption, distribution, elimination, safety profiles, therapeutic success, or failure. The presence of food can interfere with the availability or excretion of drugs in the body. Interestingly, drugs can also interfere with nutritional status, increasing or decreasing appetite and thus affecting the amount of food consumed. As of now, providing a clinically helpful definition of DNIs remains challenging. In this chapter and subsequent ones, alterations in biological processes with or without nutrients, minerals, functional foods, herbs, isolated compounds, metabolites, vitamins, beverages, supplements, etc., are considered important components of nondrug entity interactions. Our grasp of DNIs is expected to change the conceptual framework and notions of drug interactions while keeping pace with the new and emerging findings on biological systems.