As High Performance Computing (HPC) has grown considerably and is expected to grow even more, effective resource management for distributed computing sys- tems is motivated more than ever. As the computational workloads grow in quantity, it is becoming more crucial to apply efficient resource management and workload scheduling to use resources efficiently while keeping the computational performance reasonably good. The problem of efficiently scheduling workloads on resources while meeting performance standards is hard. Additionally, non-clairvoyance of job dimen- sions makes resource management even harder in real-world scenarios. Our research methodology investigates the scheduling problem compliant for HPC and researches the challenges for deploying the scheduling in real world-scenarios using state of the art machine learning and data science techniques. To this end, this Ph. D. dissertation makes the following core contributions: a) We perform a theoretical analysis of space-sharing, non-preemptive scheduling: we studied this scheduling problem and proposed scheduling algorithms with polyno- mial computation time. We also proved constant upper-bounds for the performance of these algorithms. b) We studied the sensitivity of scheduling algorithms to the accuracy of runtime and devised a meta-learning approach to estimate prediction accuracy for newly submitted jobs to the HPC system. c) We studied the runtime prediction problem for HPC applications. For this purpose, we studied the distri- bution of available public workloads and proposed two different solutions that can predict multi-modal distributions: switching state-space models and Mixture Density Networks. d) We studied the effectiveness of recent recurrent neural network models for CPU usage trace prediction for individual VM traces as well as aggregate CPU usage traces. In this dissertation, we explore solutions to improve the performance of scheduling workloads on distributed systems. We begin by looking at the problem from the theoretical perspective. Modeling the problem mathematically, we first propose a scheduling algorithm that finds a constant approximation of the optimal solution for the problem in polynomial time. We prove that the performance of the algorithm (average completion time is the constant approximation of the performance of the optimal scheduling. We next look at the problem in real-world scenarios. Considering High-Performance Computing (HPC) workload computing environments as the most similar real-world equivalent of our mathematical model, we explore the problem of predicting application runtime. We propose an algorithm to handle the existing uncertainties in the real world and show-case our algorithm with demonstrative effectiveness in terms of response time and resource utilization. After looking at the uncertainty problem, we focus on trying to improve the accuracy of existing prediction approaches for HPC application runtime. We propose two solutions, one based on Kalman filters and one based on deep density mixture networks. We showcase the effectiveness of our prediction approaches by comparing with previous prediction approaches in terms of prediction accuracy and impact on improving scheduling performance. In the end, we focus on predicting resource usage for individual applications during their execution. We explore the application of recurrent neural networks for predicting resource usage of applications deployed on individual virtual machines. To validate our proposed models and solutions, we performed extensive trace-driven simulation and measured the effectiveness of our approaches.