This review describes plant originated serine protease inhibitors (SPIs) that target or inhibit different families of serine proteases (SPs), protein-digesting enzymes of various pathogens. SPs play a crucial task in many biological events by catalyzing proteolysis that serves as mediators of signal initiation, transmission and termination of the cellular events leading to regulation of an organism's life cycle. The activity of proteases has to be closely regulated by proteinase inhibitors (PIs) to avoid the damage that proteases might cause in vivo, in the host organism. Based on the selectivity and inhibitory activity PIs are categorized into four mechanistic class viz. aspartic PI (pepstatins), serine PI (serpins), cysteine PI (cystatins) and metallocarboxy PI. Among these SPI family is the largest. Many organisms including bacteria, fungus, viruses, protists, insects and vertebrates derive their nutritional requirement from various life forms by finding a suitable host. Proteases constitute 1-5% of genomes of these infectious organisms among which SPs regulate protein synthesis, turnover and physiological functions viz. fertilization, growth and development, digestion, cell signaling or migration, immune defense, wound healing and disease propagation. SPs mediate the process of pathogenesis and/or host tissue penetration for a number of diseases in the host organisms. SPs are generally found either as constitutive components in plant storage tissues like seeds and tubers or expressed in response to pest and pathogen attack besides acting as a defense system against a wide variety of pathogens. These expressed or endogenously present SPIs can attenuate SPs with cross-protection against a wide array of protease families of pathogens like bacteria, fungus, nematodes and viruses.