Nanoscale resolution scanning ion conductance microscopy (SICM) is now at the forefront of imaging topography of biological cells even if they have complex and delicate surface structures. SICM offers several advantages over conventional high resolution and optical imaging techniques including super-resolution techniques. SICM can be performed on live cells without extensive sample preparation, and therefore it has also been successfully used to study cell signalling in combination with other biophysical and imaging techniques. Cardiac biology has greatly benefitted from the use of SICM to obtain high resolution topography images of cardiomyocytes and other cardiac cells. With the use of SICM combination techniques such as super-resolution scanning patch-clamp, SICM-FRET, SICM-LCM, etc., several underlying cell signalling pathways could be associated with cell surface structures reiterating the importance of structure as it relates to function. Combination techniques like super-resolution scanning patch-clamp and SICM-FRET for the first time provided direct evidence of the role of cellular microdomains in maintaining receptor function. It provided direct evidence for the concept that a receptor or a protein may become non-functional or become dysfunctional if it is relocated to a new microdomain from its native microdomain as usually happens in pathological cases. © 2021, The Author(s), under exclusive license to Springer Nature Switzerland AG.