In this chapter we present our semi-synthetic approach to the construction of minimal living cells. Firstly, we shortly review the advancements carried out in the last few years, especially in the field of reactions inside liposomes. Then we discuss our recent study on the investigation of minimal cell size, carried out from the perspective of synthetic biology. In particular, we examine the question of the minimal physical size of cells by using liposomes with entrapped the complete ribosomal machinery for protein expression (green fluorescence protein), and making the assumption that this size would also correspond to a full fledged cell. We have found that liposomes with radius ca. 100 nm - which is the smallest size ever considered in the literature for protein expression - are still capable of protein expression. Finally, we show how this study has provided insightful results that actually broaden our perspective and pave the way to more extensive studies on vesicle formation and encapsulation of solutes. In fact, since classic statistical analysis gives zero or negligible probability for the simultaneous entrapment of many different molecular components in one single 100 nm radius spherical compartment at the given bulk concentration, the agreement between theoretical statistical predictions and experimental data is possible by assuming that the concentration of solutes in the liposomes becomes larger by at least of a factor 20. These aspects have a great relevance in origins of life scenarios, where the formation of functional protocells is a decisive - yet not fully understood - event. We provide a final discussion on possible mechanisms and on the experimental investigations we would like to carry out in the near future. © 2011 Springer Science+Business Media B.V.