Saccharomyces cerevisiae can survive extreme desiccation, but the molecular mechanisms are poorly understood. To define genes involved in desiccation tolerance, two complementary genome-wide approaches, phenomics and transcriptomics, have been used, together with a targeted analysis of gene deletion mutants tested individually for their ability to survive drying. Genome-wide phenotypic analyses carried out on a pooled library of single-gene deletion mutants subjected to three cycles of desiccation and re-growth to post-diauxic phase identified about 650 genes that contributed to strain survival in the drying process. Air-drying desiccation-tolerant post-diauxic phase cells significantly altered transcription in 12% of the yeast genome, activating expression of over 450 genes and down-regulating 330. Autophagy processes were significantly over-represented in both the phenomics study and the genes up-regulated on drying, indicating the importance of the clearance of protein aggregates/damaged organelles and the recycling of nutrients for the survival of desiccation in yeast. Functional carbon source sensing networks governed by the PKA, Tor and Snf1 protein kinase complexes were important for the survival of desiccation, as indicated by phenomics, transcriptomics, and individual analyses of mutant strains. Changes in nitrogen metabolism were evident during the drying process and parts of the environmental stress response were activated, repressing ribosome production and inducing genes for coping with oxidative and osmotic stress.