Physician-scientists, with in-depth training in both medicine and research, are uniquely poised to address pressing challenges at the forefront of biomedicine. In recent years, a number of organizations have outlined obstacles to maintaining the pipeline of physician-scientists, classifying them as an endangered species. As in-training and early-career physician-scientists across the spectrum of the pipeline, we share here our perspective on the current challenges and available opportunities that might aid our generation in becoming independent physician-scientists. These challenges revolve around the difficulties in recruitment and retention of trainees, the length of training and lack of support at key training transition points, and the rapidly and independently changing worlds of medical and scientific training. In an era of health care reform and an environment of increasingly sparse NIH funding, these challenges are likely to become more pronounced and complex. As stakeholders, we need to coalesce behind core strategic points and regularly assess the impact and progress of our efforts with appropriate metrics. Here, we expand on the challenges that we foresee and offer potential opportunities to ensure a more sustainable physician-scientist workforce.