High water flux and elevated rejection of salts and contaminants are two primary goals for membrane distillation (MD). It is imperative to study the factors affecting water flux and solute transport in MD, the fundamental mechanisms, and practical applications to improve system performance. In this review, we analyzed in-depth the effects of membrane characteristics (e.g., membrane pore size and distribution, porosity, tortuosity, membrane thickness, hydrophobicity, and liquid entry pressure), feed solution composition (e.g., salts, non-volatile and volatile organics, surfactants such as non-ionic and ionic types, trace organic compounds, natural organic matter, and viscosity), and operating conditions (e.g., temperature, flow velocity, and membrane degradation during long-term operation). Intrinsic interactions between the feed solution and the membrane due to hydrophobic interaction and/or electro-interaction (electro-repulsion and adsorption on membrane surface) were also discussed. The interplay among the factors was developed to qualitatively predict water flux and salt rejection considering feed solution, membrane properties, and operating conditions. This review provides a structured understanding of the intrinsic mechanisms of the factors affecting mass transport, heat transfer, and salt rejection in MD and the intra-relationship between these factors from a systematic perspective.