Abstract: In several crucial applications, domain knowledge is encoded by a system of ordinary differential equations (ODE), often stemming from underlying physical and biological processes. A motivating example is intensive care unit patients: the dynamics of vital physiological functions, such as the cardiovascular system with its associated variables (heart rate, cardiac contractility and output and vascular resistance) can be approximately described by a known system of ODEs. Typically, some of the ODE variables are directly observed (heart rate and blood pressure for example) while some are unobserved (cardiac contractility, output and vascular resistance), and in addition many other variables are observed but not modeled by the ODE, for example body temperature. Importantly, the unobserved ODE variables are ``known-unknowns'': We know they exist and their functional dynamics, but cannot measure them directly, nor do we know the function tying them to all observed measurements. As is often the case in medicine, and specifically the cardiovascular system, estimating these known-unknowns is highly valuable and they serve as targets for therapeutic manipulations. Under this scenario we wish to learn the parameters of the ODE generating each observed time-series, and extrapolate the future of the ODE variables and the observations. We address this task with a variational autoencoder incorporating the known ODE function, called GOKU-net for Generative ODE modeling with Known Unknowns. We first validate our method on videos of single and double pendulums with unknown length or mass; we then apply it to a model of the cardiovascular system. We show that modeling the known-unknowns allows us to successfully discover clinically meaningful unobserved system parameters, leads to much better extrapolation, and enables learning using much smaller training sets.