Phenylpropanoids and flavonoids are specialized metabolites frequently reported as involved in plant defense to biotic or abiotic stresses. Their biosynthetic accumulation may be constitutive and/or induced in response to external stimuli. They may participate in plant signaling driving plant defense responses, act as a physical or chemical barrier to prevent invasion, or as a direct toxic weapon against microbial or insect targets. Their protective action is described as the combinatory effect of their localization during the host’s interaction with aggressors, their sustained availability, and the predominance of specific compounds or synergy with others. Their biosynthesis and regulation are partly deciphered; however, a lot of gaps in knowledge remain to be filled. Their mode of action on microorganisms and insects probably arises from an interference with important cellular machineries and structures, yet this is not fully understood for all type of pests and pathogens. We present here an overview of advances in the state of the art for both phenylpropanoids and flavonoids with the objective of paving the way for plant breeders looking for natural sources of resistance to improve plant varieties. Examples are provided for all types of microorganisms and insects that are targeted in crop protection. For this purpose, fields of phytopathology, phytochemistry, and human health were explored.