An unexpected thread ties together a few of the articles in this issue of Cell Systems.Our cover article introduces the ontotype (Yu et al., pp. 77–88). Akin to genotype and phenotype, an individual’s genetic and physical characteristics, an ontotype is the genotype organized and aggregated using a gene ontology. Conceptually, the ontotype is a structured representation of the genotype that makes use of known hierarchical, multi-scale biological relationships to predict phenotype from genotype.A second article uses features of individual and groups of amino acids in proteins to systematically identify so called protein cis regulatory regions (Gsponer et al., pp. 89–100). Global analyses found these regulatory regions in ∼30% of human proteins, but this work represents an opening salvo rather than the final word on the subject (Gibson and Kumar, pp. 68–70).A third article looks at >2,000 extant mitochondrial genomes, comprehensively analyzes all possible combinations of gene flow between mitochondrial and nuclear genomes, and identifies factors that explain why some genes but not others, have been retained in mitochondrial genomes (Johnston and Williams, pp. 101–111). This work provides empirical evidence for a hypothesis that mitochondrial genes are retained so that each mitochondria can precisely tune its individual function to best match the cell's needs (Allen and Martin, pp. 70–72).So what do three studies on ontotypes, protein regulatory regions, and mitochondrial genomes have to do with each other? All seek to decode sequence-to-function relationships.Each harnesses a different lever, whether it be the evolutionary history of genomes, the deep collection of knowledge in an ontology, or characteristic physiochemical molecular features. Notably, this month’s Cell Systems Call highlights four studies published in other journals that advance our understanding of how mRNA sequence affects protein expression, ribosome recruitment, and protein solubility (pp. 60–61). Collectively, these studies exemplify the notion that comprehensive approaches, making use of the scale with which we can now tackle biological systems, hold much promise for addressing classic biological questions.