A large number of compounds which contain BiS2 layers exhibit enhanced superconductivity upon electron doping. Much interest and research effort has been focused on BiS2-based compounds which provide new opportunities for exploring the nature of superconductivity. Important to the study of BiS2-based superconductors is the relation between structure and superconductivity. By modifying either the superconducting BiS2 layers or the blocking layers in these layered compounds, one can effectively tune the lattice parameters, local atomic environment, electronic structure, and other physical properties of these materials. In this article, we will review some of the recent progress on research of the effects of chemical substitution in BiS2-based compounds, with special attention given to the compounds in the LnOBiS2 (Ln = La-Nd) system. Strategieswhich are reported to be essential in optimizing superconductivity of these materials will also be discussed.