Atomic Force microscopy (AFM) is becoming a prevalent tool in cell biology and biomedical studies, especially those focusing on the mechanical properties of cells and tissues. The newest generation of bio-AFMs combine ease of use and seamless integration with live-cell epifluorescence or more advanced optical microscopies. As a unique feature with respect to other bionanotools, AFM provides nanometer-resolution maps for cell topography, stiffness, viscoelasticity, and adhesion, often overlaid with matching optical images of the probed cells. This review is intended for those about to embark in the use of bio-AFMs, and aims to assist them in designing an experiment to measure the mechanical properties of adherent cells. In addition to describing the main steps in a typical cell mechanics protocol and explaining how data is analysed, this review will also discuss some of the relevant contact mechanics models available and how they have been used to characterize specific features of cellular and biological samples.