The effects of abiotic factors on organisms and on the course of evolution have long been a central interest of biology. Temperature has been extensively studied because it is a thermodynamically fundamental parameter easily manipulated in the laboratory. Variation in hydrostatic pressure is just as fundamental and just as ubiquitous an abiotic factor, since 90% of the Earth’s habitable volume lies in the deep sea, and pressure increases 1 bar per 10 m depth. However, the biological effects of pressure have received less attention than those of temperature due to the technical challenges of obtaining and experimenting with organisms from the deep sea. This work applies modern techniques in novel ways to shed light on the biochemical and biophysical mechanisms of naturally evolved cellular pressure tolerance. Ctenophores, or comb jellies, are adopted as a focal taxon. Protein sequences are predicted from mRNA transcripts and compared using a phylogenetically aware method, generating predictions that pressure- and temperature-adaptation of enzymes mostly involve interactions with ligands and water. Lipid acyl chain compositions are compared within a large, diverse set of ctenophore samples, demonstrating that depth- and cold-adaptation of ctenophore lipid composition are distinct. Biophysical characterization of ctenophore lipid membranes and their chemical components show that the maintenance of ability to change membrane topology is one of the most important components of high-pressure adaptation.