Gone are the days when solid-state NMR spectroscopy was considered to be untouchable-like as it provided unappealing spectral lines due to poor resolution and sensitivity. Introduction of a number of powerful concepts dramatically increased the resolution and sensitivity of the spectroscopy and paved numerous avenues for researchers from all walks of science. Now, the new era is harvesting the valuable technique’s applications on chemical, material, biological, and pharmaceutical systems in all types of non-isotropic phases such as single crystal, liquid crystal, fibre, powder, and amorphous. One of the most powerful solid-state NMR techniques is PISEMA, which provides very high resolution of the correlation and the precise measurement of chemical shift and heteronuclear dipolar coupling interactions. It is a combination of polarization inversion, that doubles the sensitivity, and spin exchange at the magic angle (SEMA) among dipolar coupled heteronuclear spins. The SEMA pulse sequence suppresses dipole–dipole interaction among protons and simultaneously generates a doubly rotating frame to have no role for chemical shifts of ¹H and S nuclei (such as ¹³C and ¹⁵N). The PISEMA pulse sequence has a high dipolar scaling factor, and the dipolar resolution in the PISEMA spectrum is up to 10 times higher than in spectra obtained by the conventional separated-local-field method. A 2D PISEMA spectrum can be viewed as an image that could be used to determine the secondary structure and topology of aligned molecules. In fact, this was the first solid-state NMR technique that rendered complete resolution and partial assignment of resonances, and the structure and the topology of uniformly labeled membrane proteins. Fascinated by the efficiency of PISEMA, a family of multidimensional pulse sequences has been designed to further increase the resolution and applied to study the structure of biological solids, particularly membrane-associated peptides and proteins which are increasingly important, but notorious in general to investigate. In this review, the pulse sequence, line-narrowing mechanism, experimental set-up, applications and limits of 2D PISEMA and related techniques, and different types of PISEMA spectra are discussed. Multi-dimensional solid-state NMR experiments designed based on 2D PISEMA and their applications are reviewed. A new one-dimensional ¹H-detected PISEMA pulse sequence to enhance the sensitivity of the experiment is also presented.