One of the curriculum goals of e-learning in school education is to develop learners for 21st century skills through their daily learning activities. This paper aims to discuss the research issues and policy implications critical for achieving such a curriculum goal. A review of literature in the related fields indicates that K-12 schools should take advantage of e-learning to maximize learning opportunities of learners for the development of 21st century skills. We identify six research issues critical for e-learning in school education, namely the realization of developing 21st century skills of learners; the bridging of the gap between curriculum in school and situations in society; the maximization of learning opportunities in the learning process; the collection of evidence of improvement and building awareness of progress; the assessment of 21st century skills; and the provision of teacher development for enculturating learners to develop 21st century skills. We recommend the relevant stakeholders across different countries/regions to consider policies on the goal-setting of curriculum addressing 21st century skills development and bridging gap between school and society; on the availability of digital technology for school education; on the privacy/legal issues of learning data in e-learning process; and on the teacher development for pre-service and in-service teachers.