Conventionally, eukaryotic mRNAs were thought to be monocistronic, leading to the translation of a single protein. However, large-scale proteomics has led to the identification of proteins translated from alternative open reading frames (AltORFs) in mRNAs. AltORFs are found in addition to predicted reference ORFs and noncoding RNA. Alternative proteins are not represented in the conventional protein databases, and this 'Ghost proteome' was not considered until recently. Some of these proteins are functional, and there is growing evidence that they are involved in central functions in physiological and physiopathological contexts. Here, we review how this Ghost proteome fills the gap in our understanding of signaling pathways, establishes new markers of pathologies, and highlights therapeutic targets.