The Mir-22 mission began when the crew launched on August 17, 1996, in Soyuz TM-24 and docked with the Mir two days later. Shannon Lucid was on-board Mir since she arrived with STS-76 on March 24, 1996. John Blaha joined the Mir-22 crew with the September 19, 1996, docking of STS-79. The return of STS-81 concluded a mission of experiments in the fields of advanced technology, Earth sciences, fundamental biology, human life sciences, microgravity, and space sciences, as well as send up new research experiments in these areas. Data gained from the mission supplied insight for the planning and development of the International Space Station, Earth-based sciences of human and biological processes, and the advancement of commercial technology.

Earth sciences research in ocean biochemistry, land surface hydrology, meteorology, and atmospheric physics and chemistry also were performed. Observation and documentation of transient natural and human-induced changes were accomplished with the use of passive microwave radiometers, a visible region spectrometer, a side-looking radar, and hand-held photography. Earth orbit allowed for documentation of atmospheric conditions, ecological and unpredictable events, and seasonal changes over long time periods.

Fundamental biology research continued developmental investigations that study the effects of the space environment on the biological systems of plants. Prolonged exposure to microgravity provides an ideal opportunity to determine the role gravity has on cell regulation and how this affects development and growth. Investigations under this discipline will also characterize the internal radiation environment of the Mir space station.

Human life sciences research consisted of investigations that focus on the crewmember's adaptation to weightlessness in terms of skeletal muscle and bone changes, psychological interactions, immune system function, and metabolism. In addition, environmental factors such as water quality, air quality, surface assessment for microbes, and crew microbiology were assessed. These ambitious investigations continued the characterization of the integrated human responses to a prolonged presence in space.
Space science research continued with the externally mounted Mir Sample Return Experiment (MSRE) and Particle Impact Experiment (PIE) payloads. These experiments continued to collect interstellar and interplanetary space particles to further our understanding of the origin and evolution of planetary systems and life on Earth.

The French mission CASSIOPÈE carried out physiological and neurological experiments. Some of these experiments were recorded for school lessons.

The scientific experiments of the crew were performed in biology, medicine, Earth observation and space technology. Protein Crystal Growth experiments in several apparatus were also part of the research work.

Experiments: Environmental Radiation Measurements, Greenhouse-Integrated Plant Experiments, Human Life Sciences, Assessment of Humoral Immune Function During Long Duration Space Flight, iotechnology System (BTS), Material in Devices as Superconductors (MIDAS), Commercial Generic Bioprocessing Apparatus (CGBA),

Atlantis carried the SPACEHAB double module providing additional middeck locker space for secondary experiments. During the five days of docked operations with Mir, the crews transferred water and supplies from one spacecraft to the other. A spacewalk by Jerry Linenger and one by his Russian cosmonaut crewmates occurred after the departure of Atlantis.