Despite the vast literature on the effects of root canal irrigants on the dentin characteristics, the precise effects of clinically relevant irrigation sequences remain unclear. In this review, we systematically dissect the role of different sequential irrigation approaches that are used in clinical endodontics. Using a systematic search strategy, we attempt to answer the question: 'Which irrigating sequence has the most deleterious effects on dentin structure and properties?' The effect of irrigants on the dentin composition and mechanical properties have been reviewed. A wide variety of concentrations, duration and techniques have been employed to characterize the effects of chemicals on dentin properties, thus making it impossible to draw guidelines or recommendations of irrigant sequences to be followed clinically. It was apparent that all the studied irrigation sequences potentially result in some deleterious effects on dentin such as decrease in the flexural strength, microhardness, modulus of elasticity and inorganic content and organic-inorganic ratio of the dentin. However, the literature still lacks comprehensive investigations to compare the deleterious effect of different irrigation sequences, using a wide variety of qualitative and quantitative methods. Such investigations are essential to make clinical recommendations and strategize efforts to minimize chemically-induced damage to dentin characteristics.