We present results at the interface of mammalian synthetic biology and genome editing towards gene therapy applications. We study a number of network topologies and exploit their properties to engineer tunable and robust systems. Specific topics include the following: (1) Variable gene dosage and noise are major sources of fluctuations in gene product levels in both endogenous and synthetic circuits. To mitigate gene expression variability we designed, simulated, constructed, and tested a range of regulatory circuits; (2) We use benchmarking and validation in the context of discovering features specific to direct and indirect network connectivities; (3) We introduce a methodology to control the copies and residence time of a gene product delivered in host human cells but also selectively disrupt fragments of the delivery vehicle; (4) We introduce a CRISPR/Cas9 based mechanism to target a heterozygous activating mutation of KRAS in cancer cells and show reversal of drug resistance to a small-molecule inhibitor.