This paper aims to provide an overview of the fundamentals, development, and evolution of residence time distribution (RTD) methodology and its applications to the flow and mixing of fluids (and solid particles) modeling in different systems. A concise literature analysis is followed by a succinct presentation of RTD methodology’s experimental and theoretical foundations and RTD-based mathematical modeling, highlighting its importance. An experimental demonstration of RTD diagnostics on a photochemical reactor is performed to identify the most practical locations for the inlet/outlet pipes (axial or radial) and the photochemical reactor’s ideal working posture (horizontal, vertical, or inclined) and to understand the level of mixing and to determine the fluid flow defects. Using the relevant RTD functions and the corresponding central moments, it was possible to show that short circuits and dead zones occurred in each of the six considered reactor configurations. Following these investigations, design solutions were proposed to achieve a convenient exposure time, proper mixing, and uniform irradiation inside the reactor.