What happens as a cell dies? How does the breakdown of one organelle impact other subcellular compartments and structures, and how does this lead to the death of the cell? In order to further our mechanistic understanding of how cells die, we aim to study this subcellular chain of events that occur as a cell is dying, also termed a terminal phenotype. To examine terminal phenotypes, we developed methods that integrate the Synthetic Genetic Array (SGA) method with high-content screening (HCS) to enable the high-throughput, quantitative assessment of changes in subcellular morphology that occur as a cell is dying. We introduce fluorescent markers of key subcellular compartments into strains carrying temperature-sensitive (ts) alleles of essential genes, and then image cells using high-throughput confocal microscopy. We introduced a panel of 23 diagnostic GFP markers, which monitor major compartments and functions in the cell, into a representative array of 384 different ts mutants using SGA, and imaged the resulting mutants over 24 hours at the non-permissive temperature. Markers tailored towards observing cell death pathways include the metacaspase Mca1-GFP, the endonuclease Nuc1-GFP, and the putative necrosis factor Nhp6a-GFP. This analysis generates rich phenotypic profiles of essential gene mutants that capture the changes in subcellular morphology that span the time from first inactivation of the gene product to the death of the cell. Preliminary results indicate that terminal phenotypes are temporally dynamic, reflecting multiple early changes in subcellular morphology that tend to be specific to the mutated gene, and later defects that are more generally associated with cell death. Furthermore, mutants that display defects in multiple subcellular compartments point towards possible unexplored functional connections between subcellular compartments and structures. These assays will provide us with new information that will allow us to determine the mechanisms behind terminal phenotypes, and to gain further insight into the functional wiring diagram of the cell.