The not-coding regions of the genome describe sequences that do not have a history of transcription. They are also called ‘dark matter’ of the genome. Here we present a working hypothesis for finding novel anti-malarial peptides from such regions of the yeast genome that encode neither RNA nor protein. This is based on our previous experimental work where not-coding DNA sequences were artificially expressed leading to protein expression and phenotypic outcome. In this study, we explored the vast not-coding DNA space of Saccharomyces cerevisiae in search of novel antimalarial peptides. Given the lack of effective therapeutic solutions against malaria, there is an urgent unmet requirement to find novel antimalarial drugs and targets. Our initial efforts to find novel anti-malarial peptides have led to unexpected and interesting results. However, our work is preliminary and is based on computational studies only. In future, more computational and experimental work is needed to establish therapeutic potential of synthetic peptides that have origins in the not-coding genome space.