Cells in a functional tissue display a highly interactive relation with their neighboring cells and associated biochemical milieu. Serious disruption in the existing homeostatic balance in the extra-cellular matrix (ECM) may lead to abnormal response by the cells. With insufficient understanding of Cell-ECM interaction and in absence of simple tools for in vitro cell-culture in 3D, we still have to rely on the data generated by growing cells in 2D. In order to comprehend Cell-ECM dynamics it is important to recreate in vivo like microenvironment in 3D. Senescence and loss of function commonly observed in cells cultured in 2D are expected to be surmounted using such tools. Unlike prevailing belief that 3D culture is required only for tissue engineering (TE) and regenerative medicine, simple and easy to handle tools for ex vivo 3D culture may lead to greater impact. With the potential to improve our understanding about cellular behavior, both in normal and abnormal surroundings, they may eventually influence the diagnosis. Here we discuss some of the tools for cell culture in 3D, made available through novel cell-interactive ECM analog technology.