In situ experimentation in “thick” specimens in HVEM does not only necessitate an adapted equipment, but also presents various specific aspects such as the determination of the mechanical conditions (local stress) of the in situ tensile tests, the identification of large extension (grain scale) mesoscopic dislocation patterns, and the imaging of individual defects. This latter problem of the specificity of defect imaging in HVEM is especially emphasized and practical examples are given and discussed with reference to the theory of contrast. The major importance of a better understanding and approach of all these specific problems is even further justified by the recent development of more versatile, either high resolution (≈0.1 nm) or field emission source, transmission, and scanning transmission (“thick” specimen observation, microdiffraction) HVEM.