Heavy metal and metalloid pollutants in our environment are among the most concerning types of contaminations. Major chronic diseases in humans such as renal and cardiovascular diseases, and neurological decline, are strongly associated with heavy metals and metalloids. Therefore, investigation and understanding the molecular mechanisms of cellular responses and detoxification processes that overcome the toxicity of these compounds in living organisms is very important. To date, several genes are identified to play central roles in cellular detoxification process. The expression of such genes can be influenced at both the transcriptional and/or translational levels by the heavy metals. As a fundamental step in the gene expression pathway, we focused on the regulation of translation initiation under stress imposed by heavy metals and metalloids. Although a wealth of information exists on the process of eukaryotic translation, a comprehensive understanding of regulation of translation initiation under stress conditions is lacking. The growing list of novel factors affecting this process further indicate the existence of other novel players, which are yet to be discovered. In the current study, we sought out to identify novel genes encoding regulatory factors known that affect yeast translation initiation during stress when general translation seems to be shut down. Utilizing systems biology techniques, we investigated the effect of specific gene deletions under heavy metal and metalloid conditions on the general process of translation and internal initiation of translation (an alternative mode of translation mediated by specific RNA structures). We explicitly investigated the role of four of identified potential translation regulating genes based on their activity in heavy metals and metalloids sensitivity. We also performed a high-throughput plasmid-based screening of a library of non-essential gene deletion strains (~4500), using the baker's yeast (Saccharomyces cerevisiae) as our model organism to identify novel genes that are involved in internal translation initiation. To this end, we identified dozens of potential novel genes that may be involved in internal translation initiation. We further investigated the role of five potential factors to support their newly identified activity.