Identifying all essential genomic components is critical for the assembly of minimal artificial life. In the genome-reduced bacterium Mycoplasma pneumoniae, we found, that small ORFs (smORFs; <100 residues), accounting for 10% of all ORFs, are the most frequently essential genomic components (53%). Essentiality of smORFs may be explained by their function as members of protein and/or DNA/RNA complexes. In larger proteins, essentiality applied to individual domains and not entire proteins, a notion we could confirm by expression of truncated domains. The fraction of essential non-coding RNAs non-overlapping with essential genes is 5% higher than of non-transcribed regions (0.9%), pointing to the important functions of the former. The data highlights the minimal genome (33%, 269410 bp of M. pneumoniae genome), with an unexpected hidden layer of smORFs with essential functions.