Apoptosis, the major form of programmed cell death (PCD), is executed by caspases. However, activation of caspases can also promote a variety of vital cellular processes. Furthermore, cell death can sometimes proceed in the absence of apoptotic caspases by triggering alternative cell death (ACD) pathways. The main goal of my proposal is to delineate the molecular mechanisms, pathways and components underlying three distinct, evolutionarily conserved, cellular destruction processes, all associated with the Drosophila sperm life cycle, and to screen blood DNA samples from fertility clinics for mutations in human homologous genes. The first process, termed germ cell death (GCD), eliminates about 25% of the pre-meiotic germ cells through an ACD pathway. In the second process, the bulk cytoplasmic contents of the terminally differentiating spermatids are removed in a process called ‘individualization’, which involves active caspases. The third process occurs immediately after fertilization to selectively eliminate the sperm mitochondrial derivative. Similar cellular processes are also instrumental for the development and homeostasis of a variety of tissues and organs in essentially all multicellular organisms. Therefore, not only will this study enhance our understanding of male germ cell maturation and function, this unique system also provides an opportunity to study these important cellular processes using physiological conditions. The extraordinary degree of anatomical and molecular conservation of spermatogenesis in animals with flagellated sperm also signifies the extension of these studies to human patients. Although human infertility is a major health problem affecting 7% of men world-wide, we are still rather ignorant about the genetic causes of male infertility. My proposed approach, therefore, is feasible and efficient, and can overcome technical, practical, and ethical limitations associated with large-scale studies in humans.