As humanity continues to push toward interplanetary travel and beyond, short- and long-term adaptation of the human body to extreme environmental conditions in space remains a fundamental concern. An astronaut experiences physically and mentally enduring situations like microgravity, extreme heat or cold, radiation, isolation, and other unforeseen technical challenges. The assessment of clinical conditions—the specific task of Clinical Pathology—during spaceflights is becoming a relevant priority. Defining a strategy to establish a sound analytical approach is among the topics of the present volume. Namely, we are trying to assess those parameters to identify the “fingerprint” of specific biological (complex) processes, including metabolic, immunologic, protein/genetic and signaling pathways, in order to depict a comprehensive, systemic model able to provide clear explanations and preventative health scenarios. To address such a challenge, an impressive technological endeavor is going on to develop innovative diagnostic tools, medical devices and infrastructures for developing remote sensing and medical support, given that medical capabilities are inherently limited during spaceflights.