This is a reference for using GitHub as a project management tool. I will be using GitHub's beta project which has slightly different functionality than the default project.
For those that have used other project management tooling, issues are akin to JIRA stories or trello cards. Per GitHub's own definition: Use GitHub Issues to track ideas, feedback, tasks, or bugs for work on GitHub.
Think of an issue as the place to track work (e.g. development) that is happening within the project.
Issues are scoped to a repository. Knowing this will help you figure out which of the following paths will be most convenient for managing them.