The in vivo and in silico understanding of genomes and networks in cellular and multicellular systems is essential for drug discovery for multicellular diseases. In silico methodologies, when integrated with in vivo engineering methods, lay the groundwork for understanding multicellular organisms and their genomes. The quest to construct a minimal cell can be followed by designed, minimal multicellular organisms. In silico multicellular systems biology will be essential in the design and construction of minimal genomes for minimal multicellular organisms. Advanced methodologies come to light that can aid drug discovery. These novel approaches include multicellular pharmacodynamics and networked multicellular pharmacodynamics.