Almost all the knowledge empowered applications rely upon accurate knowledge, which has to be either collected manually with high cost, or extracted automatically with unignorable errors. In this paper, we study 20 Questions, an online interactive game where each question-response pair corresponds to a fact of the target entity, to acquire highly accurate knowledge effectively with nearly zero labor cost. Knowledge acquisition via 20 Questions predominantly presents two challenges to the intelligent agent playing games with human players. The first one is to seek enough information and identify the target entity with as few questions as possible, while the second one is to leverage the remaining questioning opportunities to acquire valuable knowledge effectively, both of which count on good questioning strategies. To address these challenges, we propose the Learning-to-Ask (LA) framework, within which the agent learns smart questioning strategies for information seeking and knowledge acquisition by means of deep reinforcement learning and generalized matrix factorization respectively. In addition, a Bayesian approach to represent knowledge is adopted to ensure robustness to noisy user responses. Simulating experiments on real data show that LA is able to equip the agent with effective questioning strategies, which result in high winning rates and rapid knowledge acquisition. Moreover, the questioning strategies for information seeking and knowledge acquisition boost the performance of each other, allowing the agent to start with a relatively small knowledge set and quickly improve its knowledge base in the absence of constant human supervision.