As plants lack a circulatory system and adaptive immune system, they have evolved their own defense systems distinct from animals, in which each plant cell is capable of defending itself from pathogens. Plants induce a number of defense responses, which are triggered by a variety of molecules derived from pathogenic microorganisms, referred to as microbe-associated molecular patterns (MAMPs), including peptides, proteins, lipopolysaccharide, β-glucan, chitin, and ergosterol. The interaction between plants and chemicals in the context of plant defense represents a “natural” and simple model for chemogenomics, at the intersection between chemical and biological diversities. For protection of crop plants from diseases, it has been shown to be effective to stimulate the plant immunity by chemical compounds, the so-called “plant defense activators”. Combinatorial chemistry techniques can be applied to the search for novel plant defense activators, but it is essential to establish an efficient and reliable screening system suitable for library screening. For studies of the plant immune system, it is difficult to use isolated proteins as biological targets because the receptors for MAMP recognition are largely unknown and even the receptors identified so far are transmembrane proteins. Therefore, screening for novel peptides acting on MAMP receptors from combinatorial libraries must rely on a solution-phase assay using cells as the biological targets. In this review, we introduce the cell-based lawn format assay for identification of peptides acting as plant defense activators from combinatorial peptide libraries. The requirements and limitations in constructing the screening system using combinatorial libraries in the studies of plant sciences are also discussed.