In this review we focus on applications of alkyl orthoesters as valuable and efficient substrates to perform various classes of two-component and multi-component organic reactions. The article has classified them according to two aspects, which are: (i) a focus on the reaction medium (solvent-free conditions, aqueous media, and organic solvents); and (ii) an examination of product structures. Reaction accomplishment under solvent-free conditions is an eco-friendly process with the absence of volatile toxic solvents, which puts it in line with green chemistry goals. Water is an interesting choice in organic transformations due to its inexpensiveness and safety. The authors hope their assessment will help chemists to attain new approaches for utilizing alkyl orthoesters in various organic synthetic methods. The review covers the corresponding literature up to the beginning of 2020.