Hemostasis is dependent upon the successful recruitment and activation of blood platelets to the site of a breach in the vasculature. Platelet activation stimulates the rapid reorganization of the cortical actin cytoskeleton, resulting in the transformation of platelets from biconcave disks to fully spread cells. During this process, platelets extend filopodia and generate lamellipodia, resulting in a dramatic increase in the platelet surface area. Kohler-illuminated Nomarski Differential Interference Contrast microscopy has proved an effective tool to characterize platelet morphological changes in real time, and provides a useful tool to identify genetic and pharmacological regulators of platelet function.