Global gene expression of Synechocystis sp. PCC 6803 encapsulated in silica gel was examined by microarray analysis. Cultures were encapsulated in gels derived from aqueous precursors or from alkoxide precursors and incubated under constant light for 24 h prior to RNA extraction. Cultures suspended in liquid media were exposed to 500 mM salt stress and incubated under identical conditions for comparison purposes. The expression of 414 genes was significantly altered by encapsulation in aqueous-derived gels (fold change ≥1.5 and P value < 0.01), the expression of 1,143 genes was significantly altered by encapsulation in alkoxide-derived gels, and only 243 genes were common to both encapsulation chemistries. Additional qRT-PCR analyses of four selected genes, ggpS, cpcG2, slr5055, and sll5057, confirmed microarray results for those genes. These results illustrate that encapsulation stress is quite different than salt stress in terms of gene expression response. Furthermore, a number of hypothetical and unknown proteins associated with encapsulation and alcohol stress have been identified with implications for improving encapsulation protocols and rationally engineering microorganisms for direct biofuel production.